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RELATÓRIO DE ACTIVIDADE 2011
INDEX
Introdução ao Relatório de Actividade ............................................................................................................ 3
General Objectives .......................................................................................................................................... 5
Scientific Productivity ...................................................................................................................................... 6
Other Activities .............................................................................................................................................. 13
Research Groups ............................................................................................................................................ 17
Cancer Genetics ...................................................................................................................................... 18
Population Genetics ............................................................................................................................... 29
Cancer Biology ........................................................................................................................................ 35
Carcinogenesis ........................................................................................................................................ 42
Cancer Drug Resistance .......................................................................................................................... 46
Proteolysis in diseases ............................................................................................................................ 49
Genetic Diversity .................................................................................................................................... 52
Tumor Molecular Models ....................................................................................................................... 55
Post-Graduation Unit ..................................................................................................................................... 57
Outreach Activities ........................................................................................................................................ 58
Science Diffusion ................................................................................................................................... 59
Public Awareness of Cancer .................................................................................................................. 60
IPATIMUP Diagnostics ................................................................................................................................... 61
Internal Services ............................................................................................................................................ 66
Sequencing Service ................................................................................................................................ 67
Proteomics Service ................................................................................................................................ 68
Animal Model Service ............................................................................................................................ 70
Cell Lines Bank ....................................................................................................................................... 72
Technical Body ....................................................................................................................................... 73
Core Services ................................................................................................................................................. 74
Informatics ............................................................................................................................................ 75
Secretary General ................................................................................................................................. 77
Programs Office .................................................................................................................................... 79
ANNEXES ........................................................................................................................................................ 80
Recent PhDs .......................................................................................................................................... 81
Research Projects ................................................................................................................................. 83
Scientific Papers .................................................................................................................................... 86
Members of IPATIMUP at Editorial Boards........................................................................................... 95
2
INTRODUÇÃO AO RELATÓRIO DE ACTIVIDADE
O ano de 2011 foi marcado pela crise política e económica do País, que se reflectiu negativamente na actividade do IPATIMUP, quer
na estagnação de processos que esperávamos terem progredido - criação da Unidade Orgânica de Investigação da (Fundação)
Universidade do Porto e início da construção do edifício do I3S com o projecto já aprovado pelo QREN - quer na incerteza, já
recorrente mas muito agudizada em 2011, quanto ao financiamento do Laboratório Associado.
Apesar de ter sido assinado o Contrato de Renovação do Estatuto de Laboratório Associado para a década 2011-2020, vemos com
grande preocupação a alteração na modalidade de financiamento da Fundação para a Ciência e a Tecnologia para a parte estrutural
do Laboratório Associado. O valor anteriormente recebido como Financiamento Plurianual passou a ser realizado no enquadramento
de um projecto de investigação, denominado Projecto Estratégico. Este projecto foi aprovado tarde e com elevado prejuízo
orçamental para o IPATIMUP. Em candidatura, o IPATIMUP solicitou um orçamento de 1.777 mil euros para cada ano de 2011 e
2012, correspondente ao valor executado e justificado à FCT no ano de 2010. O IPATIMUP tem vindo recorrentemente a justificar
despesa neste nível de valor à FCT, demonstrando ser o valor necessário ao regular funcionamento do IPATIMUP.
O resultado de avaliação global da candidatura foi excelent, pontuação atribuída a todos os critérios com excepção do critério C Feasibility of the plan of work and reasonableness of the budget, onde obteve very good. O painel recomendou a redução do
orçamento para 1.227 mil euros em cada ano de 2011 e 2012, correspondendo exactamente este valor ao atribuído em 2010 e ao
mesmo nível do ano de 2005. O IPATIMUP apresentou recurso logo após a comunicação da avaliação, no final de Maio de 2011. Em
Setembro de 2011, na ausência de resposta e sem perspectivas da mesma, com uma descida significativa dos recursos de tesouraria
e com o risco iminente de não recuperação do valor de 1.227 euros cativados pela FCT para o IPATIMUP no ano de 2011, a Direcção
do IPATIMUP foi obrigada a desistir do recurso.
Em 2011, ano de grande instabilidade política geral e de grande instabilidade em políticas de ciência e tecnologia, foi realizado um
esforço suplementar na procura de fontes alternativas de financiamento, colocando-se-nos como preocupação especial a
manutenção de recursos humanos vitais ao desenvolvimento científico do IPATIMUP:
- foi apresentada candidatura ao Concurso público SAESCTN-PIIC&DT/1/2011 - Programas Integrados de IC&DT - do Eixo Prioritário I Competitividade, Inovação e Conhecimento do ON.2 - Programa Operacional Regional do Norte, com o título “Translational research
on cancerous and pre-cancerous lesions”. Esta candidatura prevê a realização de um Programa Integrado composto por três linhas Cancer Invasion, Microenvironment, metabolism and cancer e Differentiation in cancer with emphasis on glycoproteome
alterations – para a contratação de 18 investigadores doutorados. O objectivo principal do Programa Integrado é o desenvolvimento
de estratégicas terapêuticas orientadas para o doente, que poderão contribuir para melhoria nos tratamentos com minimização de
efeitos secundários adversos nos doentes com cancro. O Programa coloca especial ênfase na investigação de translação – translação
de descobertas de investigação básica incluindo a validação científica dos resultados experimentais em amostras de doentes com
cancro – contribuindo assim para o desenvolvimento e validação de novas terapias.
- foram submetidas três candidaturas ao Programa Harvard Medical School, todas com o objectivo de desenvolvimento de novas
ferramentas terapêuticas e em parceria com outras instituições (INEB, IBMC, Hospital S. João e ITQB).
- foram submetidas duas candidaturas ao European Research Council Starting Grants, uma candidatura à Indigo Research Foundation
e duas candidaturas ao Programa Marie Curie Initial Training Network , para além de outras a calls do Sétimo Programa-Quadro
Europeu de Investigação.
A produção científica bateu em 2011 todos os recordes. Publicámos 186 novos artigos em revistas internacionais indexadas, 70 dos
quais em revistas com Factor de Impacto superior a 3 (ver Relatório).
Para além dos objectivos específicos de cada grupo, os objectivos globais de longo prazo do IPATIMUP no sentido de manter a
proeminência internacional na investigação relacionada com os mecanismos envolvidos na progressão do cancro gástrico e cancro da
tireóide foram realizados, mantendo o IPATIMUP como uma das melhores instituições mundiais nestes dois domínios. Durante o ano
de 2011 o IPATIMUP reformulou as suas linhas científicas adaptando-as ao papel que o Instituto desempenha tanto a nível nacional
como internacional. Desde 2011 o IPATIMUP apresenta 3 linhas científicas fulcrais:

Linha 1) “Translational oncology: from early diagnosis to therapy selection”,

Linha 2) “Epithelial neoplastic and preneoplastic lesions”,

Linha 3) “Population genetics: origin and evolution of genetic diversity in health and disease”
Em 2011, realizaram em Universidades Portuguesas e Estrangeiras as suas Provas de Doutoramento 15 elementos do IPATIMUP.
3
Atendendo ao crescimento exponencial do número de estudantes de doutoramentos admitidos pelo IPATIMUP enquanto instituição
de acolhimento e à degradação da situação orçamental em 2011, o IPATIMUP iniciou negociações com as Faculdades para
estabelecimento de protocolos de colaboração para actividades de ensino e de investigação. Estes protocolos têm por objectivo o
enquadramento institucional de colaborações há muitos anos iniciadas com as Faculdades - acolhimento de estudantes de
doutoramento e mestrado, realização de módulos de programas de doutoramento e mestrado, realização de estágios curriculares
para estudantes do último ano de licenciatura, participação de investigadores do IPATIMUP na leccionação de módulos – com custos
elevados de utilização de recursos próprios do IPATIMUP.
Foram aceites para financiamento catorze projectos de investigação, dos quais destacamos sete da FCT, um da indústria
farmacêutica internacional, três da Comissão Europeia (um de investigação, um de training e um de lifelong learning) e dois de
cooperação específica com o Brasil.
O IPATIMUP manteve uma estreita colaboração com o Health Cluster Portugal (HCP) - Pólo de Competitividade em Saúde, quer
isoladamente, quer em articulação com o IPO-Porto (Consórcio IPATIMUP–IPO) e o Centro Hospitalar de S. João (Protocolo de
colaboração).
O grupo de investigação do INEB “NEW Therapies” mantém-se nas instalações do IPATIMUP, ocupando um laboratório de 50m2
onde foi instalado um Centro de Bioimagem que servirá o I3S e outras instituições ligadas ao sistema de saúde, após aprovação da
candidatura ao QREN. O IPATIMUP considera este acolhimento físico fundamental para o estímulo da colaboração inter-institucional
e multidisciplinar, nomeadamente na interface de I&D Cancro e Medicina Regenerativa.
A 1st Advanced Summer School -Interrogations at the Biointerface, constituiu a 1ª edição das escolas de Verão em Cancro e
Regeneração, promovidas pelo INEB – Instituto Nacional de Engenharia Biomédica, o IPATIMUP e o IBEC - Institut de Bioenginyeria
de Catalunya, Barcelona, Espanha. A edição de 2011 teve como tópico Cancer/Regeneration Interface e contou com um conjunto de
especialistas em ambos os temas (oncologia e regeneração) que discutiram as bases biológicas de ambos os processos.
O II Scientific Retreat do I3S realizou-se na Póvoa de Varzim, em 5 e 6 de Maio de 2011, com a participação maciça dos
investigadores do IPATIMUP, tendo o IPATIMUP apresentado 59 posters e realizado 6 apresentações orais. Duas das investigadoras
do IPATIMUP (Raquel Seruca e Luisa Pereira), fizeram parte da comissão cientifica deste encontro.
O I3S promoveu, em Dezembro de 2011, a primeira avaliação científica conjunta dos 3 institutos por um painel de avaliação
internacional.
Em contra-ciclo com a conjuntura de 2011, a Unidade de Prestação de Serviços IPATIMUP Diagnósticos registou um aumento do
valor de facturação, com um crescimento notável na realização de exames na área da susceptibilidade genética.
4
GENERAL OBJECTIVES
The objectives of IPATIMUP may be divided into three major categories:
SCIENTIFIC OBJECTIVES
Besides the specific objectives of each research group, long term objectives of IPATIMUP are the following:
-
To achieve international leadership in research related to the mechanisms involved in gene-environment interactions in
cancerous and precancerous diseases;
-
To keep the world-competitive research level on gastric and thyroid carcinogenesis and to achieve international
prominence in research related to breast and colo-rectal cancer;
-
To contribute, through the results of its translational research and through partnerships with other institutions, to the
improvement of prevention and early diagnosis of cancer and for the targeted treatment of cancer patients;
-
To improve the quality of scientific production (see WEB) and of the track record of our young researchers;
-
To diversify our traditional approach to cancer research towards other models (e.g. developmental biology, experimental
animal models and regenerative medicine) using the possibilities opened by the I3S Consortium, the Consortium
IPATIMUP – Porto Cancer Institute and the development of the Tissue Banks of HS João, IPATIMUP and Porto Cancer
Institute.
EDUCATIONAL OBJECTIVES
To achieve international prominence in the advanced training of physicians and young scientists in the setting of the Foundation of
Porto University and the future Doctoral Program in Health Sciences of Porto University;
To contribute for improving the professional training of pathologists and residents in pathology, geneticists, biologists and
technicians;
To contribute, through the training of teachers and their students, for improving the education for cancer prevention;
To improve the connection in all of these activities with INEB and IBMC.
SERVICE-ORIENTED OBJECTIVES
To keep the international competitive level in the diagnosis of gastric, thyroid, mammary and colorectal cancer, as well as in the
diagnosis of several familial cancer syndromes;
To increase the involvement in the activities of the recently created Health Cluster Portugal (HCP);
To use our diagnostic activities towards the reinforcement of Tissue and Tumour Banks of IPATIMUP/HS João/Porto Cancer Institute
and to consolidate the utilization of the observational findings in human material as a major trigger to proceed using mechanistic
oriented studies.
5
SCIENTIFIC PRODUCTIVITY
2011 was the best year of IPATIMUP’s life to date.
1.
The researchers of the Institute publiseh 186 papers in international indexed journals:
Paper Type
2007
2008
2009
2010
2011
Article
80
74
107
84
88
Not yet classified
74
12
10
10
24
Letter
3
6
9
4
6
Review
5
5
7
11
11
Proceedings Paper
2
1
Meeting Abstract
Editorial Material
3
2
6
1
30
3
1
1
1
4
4
Epub ahead of print
15
Article; Proceedings Paper
2.
1
1
70 of the aforementioned 186 papers were published in journals with an Impact factor equal or superior to 3 (IF≥3), and
18 papers were published in journals with IF≥6:
90
60
>6
0-1
1-3
3-6
30
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
3.
The rate of citations of IPATIMUP papers went on being very high both in “Clinical Medicine” and in “All Fields”:
MOST CITED INSTITUTIONS IN CLINICAL MEDICINE
Institution: IPATIMUP
Citation Data (In 5-year Intervals):
5-year Intervals:
2001-2005
2002-2006
2003-2007
2004-2008
2005-2009
2006-2010
2007-2011
# of Papers
42
45
37
41
38
32
29
Times Cited
554
494
432
346
352
421
226
13.19
10.97
11.67
8.43
9.26
13.15
7.79
Citations per Paper
6
MOST CITED INSTITUTIONS IN ALL FIELDS
Institution: IPATIMUP
Citation Data (In 5-year Intervals):
5-year Intervals:
2001-2005
2002-2006
2003-2007
2004-2008
2005-2009
2006-2010
2007-2011
# of Papers
49
60
52
56
59
55
44
Times Cited
565
525
506
437
515
609
331
11.53
8.75
9.73
7.80
8.73
11.07
7.52
Citations per Paper
FIELD RANKINGS FOR IPATIMUP
View
Field
Papers
CLINICAL MEDICINE
1
ALL FIELDS*
4.
Citations
Citations Per Paper
79
2,178
27.57
110
2,573
23.39
Reflecting the excellent impact of IPATIMUP’s papers, 12 of the 19 TOP PAPERS for University of Porto in Clinical Medicine
were co-authored by researchers for IPATIMUP:
TOP PAPERS FOR UNIV PORTO IN CLINICAL MEDICINE (March 2012)
1 Citations: 424
Title:
HOW TO DIAGNOSE DIASTOLIC HEART FAILURE: A CONSENSUS STATEMENT ON THE DIAGNOSIS OF HEART FAILURE
WITH NORMAL LEFT VENTRICULAR EJECTION FRACTION BY THE HEART FAILURE AND ECHOCARDIOGRAPHY
ASSOCIATIONS OF THE EUROPEAN SOCIETY OF CARDIOLOGY
Authors:
PAULUS WJ; TSCHOPE C; SANDERSON JE; RUSCONI C; FLACHSKAMPF FA; RADEMAKERS FE; MARINO P; SMISETH
OA; DE KEULENAER G; LEITE-MOREIRA AF; BORBELY A; EDES I; HANDOKO ML; HEYMANS S; PEZZALI N; PIESKE
B; DICKSTEIN K; FRASER AG; BRUTSAERT DL
Source:
EUR HEART J
28 (20): 2539-2550 OCT 2007
Addresses:
Vrije Univ Amsterdam, Med Ctr, Physiol Lab, Van Boechorststr,7, NL-1081 BT Amsterdam, Netherlands.
Vrije Univ Amsterdam, Med Ctr, Physiol Lab, NL-1081 BT Amsterdam, Netherlands.
Charite Univ Kliniken, Berlin, Germany.
Keele Univ, Stoke On Trent, Staffs, England.
St Orsola Marcello Malpighi Hosp, Brescia, Italy.
Univ Erlangen Nurnberg, D-8520 Erlangen, Germany.
Univ Leuven, Louvain, Belgium.
Univ Studi Piemonte Orientale, Novara, Italy.
Univ Oslo, Rikshosp, N-0027 Oslo, Norway.
Middleheim Ziekenhuis, Antwerp, Belgium.
Univ Porto, P-4100 Oporto, Portugal.
UDMHSC, Inst Cardiol, Debrecen, Hungary.
Univ Hosp Maastricht, Maastricht, Netherlands.
Univ Gottingen, D-3400 Gottingen, Germany.
Stavanger Univ Hosp, Stavanger, Norway.
Cardiff Univ, Cardiff, Wales.
Field:
CLINICAL MEDICINE
2 Citations: 312
Title:
COLOR AND GENOMIC ANCESTRY IN BRAZILIANS
Authors:
PARRA FC; AMADO RC; LAMBERTUCCI JR; ROCHA J; ANTUNES CM; PENA SDJ
Source:
PROC NAT ACAD SCI USA
100 (1): 177-182 JAN 7 2003
Addresses:
Univ Fed Minas Gerais, Dept Bioquim & Imunol, BR-31270901 Belo Horizonte, MG, Brazil.
Univ Fed Minas Gerais, Dept Parasitol, BR-31270901 Belo Horizonte, MG, Brazil.
Univ Fed Minas Gerais, Fac Med, BR-31270901 Belo Horizonte, MG, Brazil.
7
Univ Porto, Inst Patol & Imunol Mol, P-4200 Oporto, Portugal.
Field:
3 Citations: 277
Title:
CLINICAL MEDICINE
HELICOBACTER PYLORI AND INTERLEUKIN 1 GENOTYPING: AN OPPORTUNITY TO IDENTIFY HIGH-RISK INDIVIDUALS
FOR GASTRIC CARCINOMA
Authors:
FIGUEIREDO C; MACHADO JC; PHAROAH P; SERUCA R; SOUSA S; CARVALHO R; CAPELINHA AF; QUINT W; CALDAS
C; VAN DOORN LJ; CARNEIRO F; SOBRINHO-SIMOES M
Source:
J NAT CANCER INST
94 (22): 1680-1687 NOV 20 2002
Addresses:
Univ Porto, Inst Patol & Imunol Mol, IPATIMUP, Rua Dr Roberto Frias S-N, P-4200465 Oporto, Portugal.
Univ Porto, Inst Patol & Imunol Mol, IPATIMUP, P-4200465 Oporto, Portugal.
Delft Diagnost Lab, Delft, Netherlands.
Univ Porto, Fac Med, P-4100 Oporto, Portugal.
Univ Cambridge, Dept Oncol, Cambridge, England.
Univ Cambridge, Dept Publ Hlth, Cambridge, England.
Hosp Sao Joao, Oporto, Portugal.
Fac Med, Oporto, Portugal.
Field:
CLINICAL MEDICINE
4 Citations: 259
Title:
INTERLEUKIN 1B AND INTERLEUKIN 1RN POLYMORPHISMS ARE ASSOCIATED WITH INCREASED RISK OF GASTRIC
CARCINOMA
Authors:
MACHADO JC; PHAROAH P; SOUSA S; CARVALHO R; OLIVEIRA C; FIGUEIREDO C; AMORIM A; SERUCA R; CALDAS
C; CARNEIRO F; SOBRINHO-SIMOES M
Source:
GASTROENTEROLOGY
121 (4): 823-829 OCT 2001
Addresses:
IPATIMUP, Rua Roberto Frias S-N, P-4200 Oporto, Portugal.
Univ Porto, Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal.
Fac Sci, Oporto, Portugal.
Hosp Sao Joao, Fac Med, Oporto, Portugal.
Field:
CLINICAL MEDICINE
5 Citations: 249
Title:
TNM STAGING OF FOREGUT (NEURO)ENDOCRINE TUMORS: A CONSENSUS PROPOSAL INCLUDING A GRADING SYSTEM
Authors:
RINDI G; KLOPPEL G; ALHMAN H; CAPLIN M; COUVELARD A; DE HERDER WW; ERIKSSSON B; FALCHETTI A; FALCONI
M; KOMMINOTH P; KORNER M; LOPES JM; MCNICOL AM; NILSSON O; PERREN A; SCARPA A; SCOAZEC
JY; WIEDENMANN B; FRASCATI CONSENSUS CONFERENCE PAR
Source:
VIRCHOWS ARCHIV
449 (4): 395-401 OCT 2006
Addresses:
Univ Parma, Dipartimento Patol & Med Lab, Sez Anat Patol, Via Gramsci 14, I-43100 Parma, Italy.
Univ Parma, Dipartimento Patol & Med Lab, Sez Anat Patol, I-43100 Parma, Italy.
Univ Kiel, Dept Pathol, D-2300 Kiel, Germany.
Gothenburg Univ, Dept Surg, S-41124 Gothenburg, Sweden.
Royal Free Hosp, Dept Internal Med, London NW3 2QG, England.
Hop Beaujon, Dept Pathol, Clichy, France.
Dept Internal Med, Rotterdam, Netherlands.
Univ Uppsala Hosp, Dept Endocrinol, Uppsala, Sweden.
Univ Florence, Dept Internal Med, Florence, Italy.
Univ Verona, Dept Surg, I-37100 Verona, Italy.
Kantonsspital, Dept Pathol, Baden, Switzerland.
Univ Bern, Dept Pathol, CH-3000 Bern, Switzerland.
Univ Porto, Dept Pathol, Sch Med, P-4100 Oporto, Portugal.
Univ Porto, IPATIMUP, P-4100 Oporto, Portugal.
Glasgow Royal Infirm, Dept Pathol, Glasgow G4 0SF, Lanark, Scotland.
Gothenburg Univ, Dept Pathol, S-41124 Gothenburg, Sweden.
Univ Spital Zurich, Dept Pathol, Zurich, Switzerland.
Univ Verona, Dept Pathol, I-37100 Verona, Italy.
Univ Lyon, Dept Pathol, Lyon, France.
Dept Internal Med, Berlin, Germany.
Field:
CLINICAL MEDICINE
6 Citations: 242
Title:
A PROINFLAMMATORY GENETIC PROFILE INCREASES THE RISK FOR CHRONIC ATROPHIC GASTRITIS AND GASTRIC
CARCINOMA
8
Authors:
MACHADO JC; FIGUEIREDO C; CANEDO P; PHAROAH P; CARVALHO R; NABAIS S; ALVES CC; CAMPOS ML; VAN DOORN
LJ; CALDAS C; SERUCA R; CARNEIRO F; SOBRINHO-SIMOES M
Source:
GASTROENTEROLOGY
125 (2): 364-371 AUG 2003
Addresses:
Univ Porto, Inst Mol Pathol & Immunol, Rua Dr Roberto Frias S-N, P-4200465 Oporto, Portugal.
Univ Porto, Inst Mol Pathol & Immunol, P-4200465 Oporto, Portugal.
Fac Med, Oporto, Portugal.
Delft Diagnost Lab, Delft, Netherlands.
Hosp Sao Joao, Oporto, Portugal.
Field:
CLINICAL MEDICINE
7 Citations: 192
Title:
MOLECULAR EVOLUTION OF BREAST CANCER
Authors:
SIMPSON PT; REIS-FILHO JS; GALE T; LAKHANI SR
Source:
J PATHOL
205 (2): 248-254 JAN 2005
Addresses:
Univ Queensland, Sch Med, Mayne Med Sch, Herston Rd, Brisbane, Qld 4006, Australia.
Inst Canc Res, Breakthrough Toby Robins Breast Canc Res Ctr, London SW3 6JB, England.
Univ Porto, IPATIMUP, Inst Mol Pathol & Immunol, Oporto, Portugal.
Univ Minho, Sch Hlth Sci, Braga, Portugal.
Univ Queensland, Royal Brisbane & Womens Hosp, Sch Med, Brisbane, Qld, Australia.
Queensland Inst Med Res, Brisbane, Qld 4006, Australia.
Field:
CLINICAL MEDICINE
8 Citations: 187
Title:
BIOELECTRICAL IMPEDANCE ANALYSIS PRINCIPLES AND METHODS
Authors:
KYLE UG; BOSAEUS I; DE LORENZO AD; DEURENBERG P; ELIA M; GOMEZ JM; HEITMANN BL; KENT-SMITH
L; MELCHIOR JC; PIRLICH M; SCHARFETTER H; SCHOLS AMWJ; PICHARD C
Source:
CLIN NUTR
23 (5): 1226-1243 OCT 2004
Addresses:
Univ Hosp Geneva, Clin Nutr Unit, Micheli Crest 24, CH-1211 Geneva 14, Switzerland.
Univ Hosp Geneva, Clin Nutr Unit, CH-1211 Geneva 14, Switzerland.
Graz Univ Technol, A-8010 Graz, Austria.
Univ Klinikum, Charite, Berlin, Germany.
Hosp Raymond Poincare, Garches, France.
Copenhagen Univ Hosp, Copenhagen, Denmark.
Hosp Univ Bellvitge, Barcelona, Spain.
Southampton Gen Hosp, Southampton SO9 4XY, Hants, England.
Univ Roma Tor Vergata, Rome, Italy.
Sahlgrens Univ Hosp, Gothenbury, Sweden.
Field:
CLINICAL MEDICINE
9 Citations: 183
Title:
N-TERMINAL-PRO-BRAIN NATRIURETIC PEPTIDE PREDICTS OUTCOME AFTER HOSPITAL DISCHARGE IN HEART FAILURE
PATIENTS
Authors:
BETTENCOURT P; AZEVEDO A; PIMENTA J; FRIOES F; FERREIRA S; FERREIRA A
Source:
CIRCULATION
110 (15): 2168-2174 OCT 12 2004
Addresses:
Univ Porto, Fac Med, Hosp S Joao,Serv Med B, Dept Med Interna,Unidade I&D Cardiovasc Porto, Piso 4,Alameda Prof Hernani Monteiro, P4200319 Oporto, Portugal.
Univ Porto, Fac Med, Hosp S Joao,Serv Med B, Dept Med Interna,Unidade I&D Cardiovasc Porto, P-4200319 Oporto, Portugal.
Field:
CLINICAL MEDICINE
10 Citations: 166
Title:
BIOELECTRICAL IMPEDANCE ANALYSIS - PART II: UTILIZATION IN CLINICAL PRACTICE
Authors:
KYLE UG; BOSAEUS I; DE LORENZO AD; DEURENBERG P; ELIA M; GOMEZ JM; HEITMANN BL; KENT-SMITH
L; MELCHIOR JC; PIRLICH M; SCHARFETTER H; SCHOLS AMWJ; PICHARD C
9
Source:
CLIN NUTR
23 (6): 1430-1453 DEC 2004
Addresses:
Univ Hosp Geneva, Clin Nutr Unit, CH-1211 Geneva 14, Switzerland.
Sahlgrens Univ Hosp, S-41345 Gothenburg, Sweden.
Univ Roma Tor Vergata, I-00173 Rome, Italy.
Southampton Gen Hosp, Southampton SO9 4XY, Hants, England.
Hosp Univ Bellvitge, Barcelona, Spain.
Univ Copenhagen Hosp, DK-2100 Copenhagen, Denmark.
Hosp Raymond Poincare, Garches, France.
Univ Klinikum Charite, Berlin, Germany.
Graz Univ Technol, A-8010 Graz, Austria.
Field:
CLINICAL MEDICINE
11 Citations: 157
Title:
BRCA1 DYSFUNCTION IN SPORADIC BASAL-LIKE BREAST CANCER
Authors:
TURNER NC; REIS JS; RUSSELL AM; SPRINGALL RJ; RYDER K; STEELE D; SAVAGE K; GILLETT CE; SCHMITT
FC; ASHWORTH A; TUTT AN
Source:
ONCOGENE
26 (14): 2126-2132 MAR 2007
Addresses:
Breakthrought Breast Canc Res Ctr, Chester Beatty Labs, Inst Canc Res, 237 Fulham Rd, London SW3 6JB, England.
Breakthrought Breast Canc Res Ctr, Chester Beatty Labs, Inst Canc Res, London SW3 6JB, England.
Univ Porto, Inst Mol Pathol & Immunol, IPATIMUP, P-4100 Oporto, Portugal.
Breast Pathol Lab, London, England.
Field:
CLINICAL MEDICINE
12 Citations: 149
Title:
TNM STAGING OF MIDGUT AND HINDGUT (NEURO) ENDOCRINE TUMORS: A CONSENSUS PROPOSAL INCLUDING A
GRADING SYSTEM
Authors:
RINDI G; KLOPPEL G; COUVELARD A; KOMMINOTH P; KORNER M; LOPES JM; MCNICOL AM; NILSSON O; PERREN
A; SCARPA A; SCOAZEC JY; WIEDENMANN B
Source:
VIRCHOWS ARCHIV
451 (4): 757-762 OCT 2007
Addresses:
Univ Parma, Dipartimento Patol & Med Lab, Sez Anat Patol, Via Gramsci 14, I-43100 Parma, Italy.
Univ Parma, Dipartimento Patol & Med Lab, Sez Anat Patol, I-43100 Parma, Italy.
Univ Parma, Dept Pathol, I-43100 Parma, Italy.
Univ Kiel, Dept Pathol, D-2300 Kiel, Germany.
Hop Beaujon, Dept Pathol, Clichy, France.
Stadspital Triemli, Dept Pathol, Zurich, Switzerland.
Univ Bern, Dept Pathol, CH-3000 Bern, Switzerland.
Univ Porto, Dept Pathol, Porto Med Sch, P-4100 Oporto, Portugal.
Univ Porto, IPATIMUP, P-4100 Oporto, Portugal.
Glasgow Royal Infirm, Dept Pathol, Glasgow G4 0SF, Lanark, Scotland.
Univ Gothenburg, Dept Pathol, Gothenburg, Sweden.
Tech Univ Munich, Klinikum Rechts Isar, Dept Pathol, D-8000 Munich, Germany.
Univ Verona, Dept Pathol, I-37100 Verona, Italy.
Univ Lyon, Dept Pathol, Lyon, France.
Campus Virchow Klinikum, Dept Internal Med, Berlin, Germany.
Field:
CLINICAL MEDICINE
13 Citations: 136
Title:
DISSEMINATION OF CLONALLY RELATED ESCHERICHIA COLI STRAINS EXPRESSING EXTENDED-SPECTRUM BETALACTAMASE CTX-M-15
Authors:
COQUE TM; NOVAIS A; CARATTOLI A; POIREL L; PITOUT J; PEIXE L; BAQUERO F; CANTON R; NORDMANNJ P
Source:
EMERG INFECT DIS
14 (2): 195-200 FEB 2008
Addresses:
Hosp Univ Ramon & Cajal, Dept Microbiol, Microbiol Serv, Carretera Colmenar,Km 9, Madrid 28034, Spain.
Hosp Univ Ramon & Cajal, Dept Microbiol, Microbiol Serv, Madrid 28034, Spain.
Consejo Suuper Investigac Cient, Antibiot & Virulencia Bacteriana Asociad, Undad Resistencia, Madrid, Spain.
Consorcio Investigac Biomed & Red Epidemiol & Sal, Madrid, Spain.
Hosp Bicertre, Paris, France.
Univ Calgary, Calgary, AB, Canada.
Field:
CLINICAL MEDICINE
10
14 Citations: 125
Title:
ROSUVASTATIN AFFECTING AORTIC VALVE ENDOTHELIUM TO SLOW THE PROGRESSION OF AORTIC STENOSIS
Authors:
MOURA LM; RAMOS SF; ZAMORANO JL; BARROS IM; AZEVEDO LF; ROCHA-GONCALVES F; RAJAMANNAN NM
Source:
J AMER COLL CARDIOL
49 (5): 554-561 FEB 6 2007
Addresses:
Hosp Pedro Hispano, Matosinhos, Portugal.
Univ S Carlos, Hosp Clin, Madrid, Spain.
Univ Porto, Sch Med, Oporto, Portugal.
NW Univ, Feinberg Sch Med, Chicago, IL USA.
Field:
CLINICAL MEDICINE
15 Citations: 120
Title:
METAPLASTIC BREAST CARCINOMAS ARE BASAL-LIKE TUMOURS
Authors:
REIS JS; MILANEZI F; STEELE D; SAVAGE K; SIMPSON PT; NESLAND JM; PEREIRA EM; LAKHANI SR; SCHMITT FC
Source:
HISTOPATHOLOGY
49 (1): 10-21 JUL 2006
Addresses:
Inst Canc Res, Breakthrough Toby Robins Breast Canc Res Ctr, Fulham Rd, London SW3 6JB, England.
Inst Canc Res, Breakthrough Toby Robins Breast Canc Res Ctr, London SW3 6JB, England.
Univ Minho, Sch Hlth Sci, ICVS, Life & Hlth Sci Res Inst, Braga, Portugal.
Univ Porto, IPATIMUP, Inst Mol Pathol & Immunol, Oporto, Portugal.
Univ Queensland, Mayne Med Sch, Med Res Inst, Brisbane, Qld, Australia.
Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia.
Univ Oslo, Norwegian Radium Hosp, Montebello, Norway.
Lab Salomao & Zoppi, Sao Paulo, Brazil.
Univ Porto, Fac Med, Oporto, Portugal.
Field:
CLINICAL MEDICINE
16 Citations: 84
Title:
KRAS MUTATION TESTING FOR PREDICTING RESPONSE TO ANTI-EGFR THERAPY FOR COLORECTAL CARCINOMA:
PROPOSAL FOR AN EUROPEAN QUALITY ASSURANCE PROGRAM
Authors:
VAN KRIEKEN JHJM; JUNG A; KIRCHNER T; CARNEIRO F; SERUCA R; BOSMAN FT; QUIRKE P; FLEJOU JF; HANSEN
TP; DE HERTOGH G; JARES P; LANGNER C; HOEFLER G; LIGTENBERG M; TINIAKOS D; TEJPAR S; BEVILACQUA G; ENSARI
A
Source:
VIRCHOWS ARCHIV
453 (5): 417-431 NOV 2008
Addresses:
Radboud Univ Nijmegen, Med Ctr, Dept Pathol, POB 9101, NL-6500 HB Nijmegen, Netherlands.
Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6500 HB Nijmegen, Netherlands.
Univ Munich, Dept Pathol, Munich, Germany.
Univ Porto, IPATIMUP, Inst Mol Pathol & Immunol, P-4100 Oporto, Portugal.
Fac Med Porto, Oporto, Portugal.
Hosp Sao Joao, Dept Pathol, Oporto, Portugal.
Univ Inst Pathol, Lausanne, Switzerland.
Univ Leeds, Leeds, W Yorkshire, England.
Univ Paris 06, St Antoine Hosp, Dept Pathol, Paris, France.
Odense Univ Hosp, Dept Pathol, DK-5000 Odense, Denmark.
Univ Hosp KU Leuven, Dept Pathol, Louvain, Belgium.
Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain.
Med Univ Graz, Inst Pathol, Graz, Austria.
Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 ED Nijmegen, Netherlands.
Univ Athens, Sch Med, Lab Histol & Embryol, GR-11527 Athens, Greece.
Univ Hosp Gasthuisberg, Digest Oncol Unit, B-3000 Louvain, Belgium.
Univ Pisa, Dept Oncol, Pisa, Italy.
Pisa Univ Hosp, Pisa, Italy.
Ankara Univ, Sch Med, Dept Pathol, TR-06100 Ankara, Turkey.
Field:
CLINICAL MEDICINE
17 Citations: 8
Title:
BREAST CANCER PROGNOSTIC CLASSIFICATION IN THE MOLECULAR ERA: THE ROLE OF HISTOLOGICAL GRADE
Authors:
RAKHA EA; REIS JS; BAEHNER F; DABBS DJ; DECKER T; EUSEBI V; FOX SB; ICHIHARA S; JACQUEMIER J; LAKHANI
SR; PALACIOS J; RICHARDSON AL; SCHNITT SJ; SCHMITT FC; TAN PH; TSE GM; BADVE S; ELLIS IO
Source:
BREAST CANCER RES
12 (4): art. no.-207 2010
Addresses:
Nottingham Univ Hosp NHS Trust, Dept Histopathol, Nottingham City Hosp Campus,Hucknall Rd, Nottingham NG5 1PB, England.
Nottingham Univ Hosp NHS Trust, Dept Histopathol, Nottingham NG5 1PB, England.
Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England.
Univ Calif San Francisco, Dept Anat Pathol, San Francisco, CA 94143 USA.
Univ Pittsburgh, Med Ctr, Pittsburgh, PA 15213 USA.
Univ Hosp Munster, Reference Ctr Munster, Gerhard Domagk Inst Pathol, D-48149 Munster, Germany.
Univ ASL, Osped Bellaria, Sez Anat Istol & Citol Patol M Malpighi, I-40139 Bologna, Italy.
Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic 3002, Australia.
11
Nagoya Med Ctr, Dept Pathol, Naka Ku, Nagoya, Aichi 4600001, Japan.
Inst Paoli Calmettes, Unite Anat & Cytol Pathol, F-13273 Marseille 9, France.
Univ Queensland, Mayne Med Sch, Brisbane, Qld 4006, Australia.
Hosp Univ Virgen Rocio, Serv Anat Patol, Seville 41013, Spain.
Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02115 USA.
Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA.
Harvard Univ, Sch Med, Boston, MA 02215 USA.
Univ Porto, Inst Mol Pathol & Immunol IPATIMUP, P-4200 Oporto, Portugal.
Singapore Gen Hosp, Dept Pathol, Singapore 169608, Singapore.
Prince Wales Hosp, Dept Anat & Cellular Pathol, Shatin, Hong Kong, Peoples R China.
Indiana Univ, Clarian Pathol Lab, Dept Pathol, Indianapolis, IN 46202 USA.
Indiana Univ, Clarian Pathol Lab, Dept Internal Med, Indianapolis, IN 46202 USA.
CLINICAL MEDICINE
Field:
18 Citations: 7
Title:
THE CONSOLIDATED STANDARDS OF REPORTING TRIALS (CONSORT) STATEMENT APPLIED TO ALLERGEN-SPECIFIC
IMMUNOTHERAPY WITH INHALANT ALLERGENS: A GLOBAL ALLERGY AND ASTHMA EUROPEAN NETWORK (GA(2)LEN)
ARTICLE
Authors:
BOUSQUET PJ; CALDERON MA; DEMOLY P; LARENAS D; PASSALACQUA G; BACHERT C; BROZEK J; CANONICA
GW; CASALE T; FONSECA J; DAHL R; DURHAM SR; MERK H; WORM M; WAHN U; ZUBERBIER T; SCHUNEMANN
HJ; BOUSQUET J
Source:
J ALLERG CLIN IMMUNOL
127 (1): 49-U511 JAN 2011
Addresses:
Hop Arnaud Villeneuve, Serv Malad Resp, Inserm U657, F-34295 Montpellier, France.
Univ Hosp Montpellier, Dept Resp Dis, Montpellier, France.
Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Sect Allergy & Clin Immunol, London SW7 2AZ, England.
Hosp Med Sur, Dept Allergy, Mexico City, DF, Mexico.
Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy.
Ghent Univ Hosp, Upper Airways Res Lab URL, B-9000 Ghent, Belgium.
McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada.
McMaster Univ, Dept Med, Hamilton, ON, Canada.
Creighton Univ, Dept Med, Div Allergy & Immunol, Omaha, NE 68178 USA.
Univ Porto, Biostat & Med Informat Dept, P-4100 Oporto, Portugal.
Univ Porto, Div Allergy, P-4100 Oporto, Portugal.
Aarhus Univ Hosp, Dept Resp Dis, DK-8000 Aarhus, Denmark.
Univ Aachen, Dept Dermatol, D-5100 Aachen, Germany.
Univ Porto, CINTESIS, P-4100 Oporto, Portugal.
Charite, Dept Dermatol, Allergy Ctr Charite, D-13353 Berlin, Germany.
Charite Hosp, Dept Pediat, Berlin, Germany.
Inserm 1018, CESP, Villejuif, France.
Field:
CLINICAL MEDICINE
19 Citations: 7
Title:
BASAL-LIKE AND TRIPLE-NEGATIVE BREAST CANCERS: A CRITICAL REVIEW WITH AN EMPHASIS ON THE IMPLICATIONS
FOR PATHOLOGISTS AND ONCOLOGISTS
Authors:
BADVE S; DABBS DJ; SCHNITT SJ; BAEHNER FL; DECKER T; EUSEBI V; FOX SB; ICHIHARA S; JACQUEMIER J; LAKHANI
SR; PALACIOS J; RAKHA EA; RICHARDSON AL; SCHMITT FC; TAN PH; TSE GM; WEIGELT B; ELLIS IO; REIS-FILHO JS
Source:
MODERN PATHOL
24 (2): 157-167 FEB 2011
Addresses:
Indiana Univ, Dept Pathol & Internal Med, Clarian Pathol Lab, 350 W 11th St, Indianapolis, IN 46204 USA.
Indiana Univ, Dept Pathol & Internal Med, Clarian Pathol Lab, Indianapolis, IN 46204 USA.
Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA.
Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA.
Harvard Univ, Sch Med, Boston, MA USA.
Univ Calif San Francisco, Dept Anat Pathol, San Francisco, CA 94143 USA.
Univ Hosp Munster, Reference Ctr Munster, Gerhard Domagk Inst Pathol, Munster, Germany.
Univ ASL Osped Bellaria, Sez Anat Istol & Citol Patol M Malpighi, Bologna, Italy.
Peter MacCallum Canc Ctr, Dept Pathol, Melbourne, Vic, Australia.
Nagoya Med Ctr, Dept Pathol, Nagoya, Aichi, Japan.
Inst J Paoli I Calmettes, Unite Anat & Cytol Pathol, F-13009 Marseille, France.
Univ Queensland, Clin Res Ctr, Sch Med & Pathol Queensland, Brisbane, Qld, Australia.
Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia.
Hosp Univ Virgen Rocio, Serv Anat Patol, Seville, Spain.
Univ Nottingham, Nottingham City Hosp NHS Trust, Dept Histopathol, Nottingham NG7 2RD, England.
Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
Univ Porto, Fac Med, Inst Mol Pathol & Immunol IPATIMUP, P-4100 Oporto, Portugal.
Singapore Gen Hosp, Dept Pathol, Singapore 0316, Singapore.
Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Hong Kong, Hong Kong, Peoples R China.
Canc Res UK London Res Inst, Signal Transduct Lab, London, England.
Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England.
Field:
CLINICAL MEDICINE
5.
In 2011, 15 young scientists from several fields (Medicine, Biology, Biochemistry) obtained their Doctor’s degree from
Portuguese and International Universities (see Recent PhD – page 82)
12
OTHER ACTIVITIES
OUTREACH ACTIVITIES DURING THE YEAR OF 2 011
The activities of scientific diffusion remain as one of the primary functions of IPATIMUP.
The outreach activities are organized in two Units, the Science Diffusion Unit and the Public Awareness of Cancer Unit.
In 2011:
-
Continuation of the protocol with the Education Department of Porto City Hall – Program “Porto de Crianças”;
-
Participation at the Day of the University of Porto with “hands on experience” for the public at large;
-
Continuation of the protocol with “Ciência Viva” for “Ciência Viva em Férias”;
-
Project “Open Lab” (Laboratorio Aberto) implemented in a partnership with Ciência Viva and Porto City Hall meant for the
experimental “teaching” of sciences. The Open Lab is constituted by two big labs and other logistic facilities at the Centre
of Teaching Resources of Porto’s City Hall (2800 students per year);
-
Project “Prevention and early diagnosis of cancer and precancerous lesions of cervix, stomach, breast and thyroid –
CancerMobile”, funded by EEA (ended 30 April 2011);
-
Project “Development of a medical information system about Hereditary Breast and Colorectal cancer”, funded by
Harvard Medical School Portugal Program;
-
Development of a model of inclusive education of science in a population visually impaired students, funded by Calouste
Gulbenkian Foudation;
-
Development of the project "Cancer-Educate to prevent", funded by Alto Comissariado da Saúde.
INTERNAL SERVICES AND RESOURCES
The IPATIMUP is organized in a way that common facilities, including Cold rooms, -150/-80ºC Freezers room, Cell culture,
Centrifuges’room, Incubator’s room , serve as platforms for sharing of equipment and other resources among all the Groups. The
same holds true for core facilities, including Sequencing, Proteomics, Real-time PCR, Tissue microarrays, Immunohistochemistry and
In situ hybridization.
All the above facilities are shared whenever necessary with groups of other (national and international) institutions, namely IBMC
and INEB, Porto Cancer Institute, Hospital S. João and Centre of Medicinal Chemistry (CEQUIMED – UP) of the Faculty of Pharmacy of
the University of Porto.
The small nude mice animal house of IPATIMUP which is located at Hospital S.João and the tumour banks of neuroendocrine
tumours (ReGene) and stromal tumours of the digestive tract (ReGIST) of IPATIMUP are also shared with the aforementioned
institutions.
IPATIMUP has been receiving support from some Portuguese and foreign institutions in the following fields:
-
Confocal microscopy (IBMC/INEB);
-
Flow cytometry/Cell sorting (IBMC/INEB);
-
Animal models (IBMC/INEB and Institut Pasteur, Paris, France);
-
Transgenic animal models (CABD, Sevilla,Spain);
-
DNA microarrays (Consortium for Functional Glycomics and CBM, Area Science Park, Trieste, Italy);
-
Tissue & tumour bank (Hospital S. João);
-
CGH array (Microarray facility, VUmedical centre, Amsterdam, The Netherlands);
13
-
siRNA platform (Max Planck Institute for Infection Biology, Berlin, Germany);
-
Genotyping platform (Institut Català d'Oncologia, Barcelona, Spain).
The acquisition of several pieces of equipment is necessary to keep the internal and the external services and to fulfil the plan of
development of IPATIMUP.
EXTERNAL SERVICES AND RESOURCES
In 2011, two new services were designed, the IPATIMUP Translation Unit and the IPATIMUP Innovation Unit, in response to the
increasing difficulties to get funds from the traditional agencies. The Services were formally created in February 2012.
The IPATIMUP Innovation Unit aims to create value from the commercial exploitation of intellectual property (IP) generated at
IPATIMUP and by stimulating the creation and growth of spin-off companies based at the Institute.
The IPATIMUP Translation Unit aims to constitute an interface between the industry and IPATIMUP’s research teams, potentiating
the Institutes’ scientific knowledge as a means of generating novel cooperative strategies in R&D. IPATIMUP TRANSLATION intends
to build strategic alliances with companies involved in the health sciences (pharmaceutical industry and biotechnology), food
industry, cosmetics and others, setting up IPATIMUP as a partner of excellence in research, innovation and development of novel
projects with added value.
IPATIMUP has been providing, since its creation in 1989, scientific and technical services both nationally and internationally. These
services were at first mainly concentrated in diagnostic anatomic pathology but have been extended to the fields of population and
forensic genetics (1991 – present), molecular pathology (1996- present) and molecular genetics and molecular epidemiology (1996 –
present).
These services are now concentrated in a single Unit , representing a major asset of IPATIMUP in three aspects: a) Produce valuable
material for epidemiology – and pathology-oriented research; b) Provide an excellent platform for interaction with clinicians
(essential for translation research); c) Contribute to the income of IPATIMUP.
IPATIMUP also provides external services in the fields of Proteomics, Functional genetics (Functional evaluation of germline missense
mutations of E-cadherin for European, north American, south American and Australian institutions), Genetic epidemiology
(Inflammatory diseases of the GI tract, cardiovascular diseases and neoplastic and preneoplastic diseases, also for institutions
throughout the world), and Molecular pathology (Tissue microarrays, in situ hybridization and “molecular” diagnosis for therapy
selection).
In 2010, IPATIMUP and INEB reinforced their interested on developing new methods for image analysis and created a Centre devoted
to Bioimaging. This centre have been actively functioning in 2011 and as an International Advisory Board, in which members of INEB
and IPATIMUP seat together with the CEO of BIAL and two International leaders in the area of bioimaging. The centre is a Scientific
Platform that works based on projects which are within the main research lines of the Centre. The focus will be on bioimaging in the
fields of biomaterials, regenerative therapies degenerative diseases and cancer.
IPATIMUP researchers provide consultancy services for the pathology of human tumours from more than 25 countries (200-300
cases per year), as well as molecular pathology and population/forensic genetics.
NETWORKING ACTIONS
The postdoc forum has played in 2011 an important role providing input in Institutional matters, critical mass between groups or
research projects, and pinpointing interesting external collaborators. The periodicity of the meetings is once a month. The postdoc
forum has organized 3 scientific symposia in 2011.
It has also been highlighted the integration of IPATIMUP in the I3S, IPO and HCP, and other international consortia and/or networks.
IPATIMUP researchers serve in the Boards of several Int Scientific Societies (Eur Society of Pathology- President, Eur Society of
Cytology, International Academy of Cytology- General Secretary, European Federation of Cytological Societies, President, Eur Society
of Human Genetics, Eur Helicobacter Study Group- President, Int Network of Glycobiology, ). Prof. Fátima Carneiro has been elected
in 2009 President of the European Society of Pathology (ESP). She is the President of the ESP in the period 2011-2013.
IPATIMUP members have been involved in the creation, in 1990, of EUROCELLPATH and European School of Pathology (ESP). Besides
organizing courses in Turin and Portugal, IPATIMUP members were involved in the creation of branches of ESP in Russia (2000),
Turkey (2002), Romania (2004) and Czech Republic (2006). Besides creating the branches, IPATIMUP members have been involved in
running courses in every of the aforementioned cities as well as in Turim.
14
IPATIMUP members have also been involved in the launching in 2004 of the Paris Course on Thyroid Pathology of the French Division
of IAP.
IPATIMUP members participate per year as invited speakers in more than 40 international scientific meetings;
Our researchers belong to the Editorial Board of several international journals (see page 95).
TRAINING ACTIVITIES
IPATIMUP is involved in the tutorial (hands on) training of future scientists (fellows with research initiation grants, Master and PhD
students), young physicians (residents and specialists in pathology, mainly) and lab technicians.
Besides its “own” trainees, IPATIMUP has been involved in the last years in the modular teaching of the following Graduate
Programs: Master Course on Molecular Medicine and Master Course on Molecular Oncology. Both Master Courses were organized
together with the Medical Faculty of Porto University. From October 2010 on, there will be a Master Course in “Molecular Medicine
and Molecular Oncology”. Organization and teaching of Forensic Genetics MSc, FCUP.
PHD (DOCTORAL) PROGRAMS
GABBA (Graduate Program on Basic and Applied Biology Areas) – together with the Medical Faculty, Sciences Faculty, Institute of
Biomedical Sciences (ICBAS) and IBMC. The 1st edition of GABBA took place in 1996, following the merging into a PhD Program of the
two Master Courses on Oncobiology and Human Genetics that were previously organized at IPATIMUP, with those on Immunology
(ICBAS) and Cell Biology (Medical Faculty). The IPATIMUP holds regularly some of the annual international meetings, seminars and
workshops of GABBA Molecular Medicine and Molecular Oncology for physicians based upon the merging of the pre-existing Master
Courses on the same topics – 1st edition in 2007 organized together with the Medical Faculty, ICBAS, Porto Cancer Institute and
IBMC/INEB Molecular Pathology and Molecular Genetics – 1st edition in 2007, organized together with the same partners as the
aforementioned PhD Program.
-
Biodiversity Genetics and Evolution PhD Program, FCUP
-
Biomedicine for MD's – 1st edition in 2008 organized by Gulbenkian and Champalimaud Foundation, together with
IPATIMUP.
IPATIMUP is also involved in the training of residents and specialists of pathology from several European countries, Brazil and
Mozambique (average of 8-10 MDs per year) mainly in cancer histopathology and cytopathology, and molecular pathology.
IPATIMUP is involved every year in the graduate training of technicians of Higher Education institutions (Polytechnic Institute of
Porto and Private Universities) (average of 6 technicians per year).
ORGANIZATION OF INTERNATIONAL EVENTS
IPATIMUP has been organizing every year, since 1992 and 1998, respectively, two international events one focusing on Oncobiology Porto Cancer Meeting, and the other on Population and/or Forensic Genetics - Portugaliae Genetica.
SUMMARY OF INTERNAL EVALUATIONS DURING 2011
The External Advisory Board (EAB) is presently constituted by Prof. Fred Bosman, MD, PhD, who presides, Prof. Ivan Damjanov,
MD,PhD, Prof. Angel Carracedo, Prof. Marc Mareel, MD, PhD and Prof. Fernando Lopes da Silva, MD, PhD. The EAB of the IPATIMUP
made a site visit on March 2011. IPATIMUP provided detailed progress reports of all the groups, detailed documentation of the
financial situation and detailed response to the recommendations made in the previous report, which was highly appreciated. In the
discussions preparing for the site visit the following strategic issues were identified as crucial for the further development of
IPATIMUP: What is the status of the I3S consortium project; is the position of IPATIMUP evolving favourably in the I3S structure?;
How are the new groups doing? Can additional new groups be created?; Future structure of I3S; IPATIMUP EAB membership in the
I3S EAB?
In the beginning of 2012, it was made the 2011 annual progression report of students and supervisors. This action aims at identifying
in early stage deviations of the students working plan, limitations/deficiencies or problems in the supervision.
The first visit of the External Advisory Board of I3S was made in December 19-20 2011. The EAB was constituted by Fred Bosman and
Ivan Damjanov (EAB members of IPATIMUP), James Fawcett (Cambridge), Andrés Garcia (Atlanta) and Chis Leaver (Oxford) (EAB
15
members of IBMC), James Kirkpatrick (Mainz) and Jacques Neefjes (Amesterdam) (EAB members of INEB) and Alex Quintanilha
(Rapporteur). The EAB received a written report of the Scientific Program, some details regarding the existing collaborations
between the 3 Institutes and a draft of the plans for the new facilities. They met the Rector (Prof Marques dos Santos) and two ViceRectors (Profs Jorge Gonçalves and António Cardoso) of the University of Porto, the former Minister for Science (Prof. José Mariano
Gago), the new Secretary of State for Science (Prof. Leonor Parreira), the CEO of Health Cluster Portugal (Prof. Joaquim Cunha) and
most of the members of the Conselho de Gestão e Orientação - CGO (Strategic and Managing Council) of the I3S, as well as some the
staff of the 3 Institutes involved in technology transfer, graduate programs and technology platforms. The 7 research domains were
presented at the beginning of the visit, in an abbreviated form by senior research members of the 3 Institutes. These included:
Oncobiology (Raquel Seruca), Population Biology (Luísa Pereira), Biomaterials and Regeneration (Pedro Granja), Bioimaging and
Biomedical Signals (Ana Maria Mendonça), Immunology and Infection (Didier Cabanes), Neurosciences (João Relvas) and Molecular
and Celular Biology (Sandra Ribeiro).
FUTURE INTERNAL EVALUATIONS PLAN FOR 2012
We will keep the system we have been using since the early nineties with a couple of alterations mainly induced by the formation of
the Consortia with IBMC and INEB (Consortium I3S) and Porto Cancer Institute.
The EABs of IPATIMUP, IBMC and INEB will help the respective Board of Directors to define an EAB common to the three Institutes
under the newly formed I3S.
The Board of Directors will go on paying a particular attention to the scientific productivity of the different groups, including the
public disclosure of all the data (e.g. papers, prizes, …) and the publication of regular reports on the overall results (see WEB)
We will also continue to evaluate positively (read: to stimulate and reward) intergroup and interinstitutional collaborations, projects
and papers.
The following criteria will be used to evaluate the outcomes:
-
Number (weighted by impact factor) of papers published in international peer reviewed journals in each research field
-
Number of citations obtained in the post-five year period of the publication and their ratio to the average citation index
per paper in each research field
-
Number and budget of research projects awarded in national and international context
-
Number and value of contracts and patents
-
“Prestige” indicators: editorial boards, international prizes, invitations for international conferences, chairmanships of
international scientific boards.
16
RESEARCH GROUPS
17
CANCER GENETICS
OBJECTIVES
The Cancer Genetics group is focused on the genetics of three common types of epithelial cancer: gastric, breast and colorectal.
The group aims at:
1.
identifying individuals at increased risk for cancer;
2.
identifying clinicopathological features and molecular markers occurring in the setting of familial and sporadic carcinoma;
3.
identifying signaling pathways mediated by genetic and environmental factors pivotal for tumor development. A special
interest is on the identification of the environmental and epi/genetic factors underlying cancer cell invasion, a topic of
crucial importance in cancer control.
The team aims to understand and unravel the molecular and cellular basis of cell invasion, using cancer as model system. With this
basic knowledge the team aims at developing new strategies for improving the quality of detection and treatment of invasive cancer.
The mortality rate of cancer patients strongly increases when tumor cells are able to invade neighboring tissues. Because of that,
invasion is one of the most (probably the most) appealing step(s) to develop targets for anti-cancer therapy and new methods to
detect invasive cells in an early stage of disease progression. To design efficient methods for detection of invasive tumor cells and
new therapeutic strategies targeting invasion, it is mandatory to identify key molecular/cell/ECM players in cancer. Specifically, the
group aims to unravel the mechanisms that regulate P-cadherin and E-cadherin expression, their associated cellular effects and
dependent signaling (upstream and downstream pathways) pivotal for cell invasion. Further, we aim at developing new in vivo
models that do not raise ethical issues to test new tools and new drugs impairing cancer cell invasion or survival (Drosphila and CAM
models).
The Cancer Genetics group collaborates with others namely with groups of Cancer Biology and Carcinogenesis of IPATIMUP and
NEWtherapies from INEB at IPATIMUP.
MAIN ACHIEVEMENTS
Helicobacter pylori vacA and cagA virulence factors and the progression of premalignant lesions of the stomach
Since there are no established predictive markers of progression of gastric preneoplastic lesions, we have analyzed whether H. pylori
virulence factors cagA and vacA could be used as such markers. In a long-term follow-up study carried out in a province of Spain with
a high risk for gastric cancer we have shown that infection with H. pylori strains that are cagA-positive, vacA s1, and vacA m1 or with
with strains that are simultaneously cagA-positive and vacA s1/m1 was associated with progression of gastric preneoplastic lesions.
These results suggest that H. pylori genotyping is useful for the identification of patients at high risk of progression of gastric
preneoplastic lesions and who need more intensive surveillance. (Gonzalez, Figueiredo, et al Am J Gastroenterology, 2011 and
Ferreira et al, Am J Gastroenterology, accepted) In collaboration with the groups of Carlos Gonzalez and Gabriel Capellá, Catalan
Institute of Oncology, Barcelona.
Helicobacter pylori CagA tyrosine phosphorylation motifs and gastric carcinoma development
We have characterized variation in virulence of H. pylori associated with CagA EPIYA motifs and explored its relationship with gastric
carcinoma development. We showed that infection with strains harboring =2 CagA EPIYA C motifs was associated with the presence
of surface epithelial damage, and was associated with atrophic gastritis and gastric carcinoma. Furthermore, the magnitude of risk
for atrophic gastritis and for gastric carcinoma increased with increasing number of EPIYA C motifs. These results suggest that the
characterization of the number of H. pylori EPIYA C motifs may be important to better define gastric carcinoma risk. (Ferreira et al,
Histopathology, accepted).
Assessment of the effects of DHA on Helicobact pylori growth and colonization in vitro and in vivo
We have demonstrated that DHA decreases H. pylori growth in vitro in a dose-dependent way, and is able to inhibit H. pylori gastric
colonization in vivo. Furthermore, the addition of DHA to standard treatment resulted in lower recurrence of H. pylori infection in a
mouse model. These observations may pave the way to the evaluation of DHA as a co-adjuvant agent in H. pylori eradication
treatment. (Correia et al, PlosOne, accepted). In collaboration with the groups of Eliette Touati, Institut Pasteur, Paris.
A novel method for genotyping clarithromycin resistance in Helicobacter pylori
We have proposed and optimized a new genotyping method to detect clarithromycin resistance in clinical samples, based on
fluorescent in situ hybridization (FISH) using peptide nucleic acid probes (PNA). The PNA-FISH based method was shown to have a
high sensitivity and specificity for detection of clarithromycin resistance in H. pylori cultured isolates, and also in clinical samples such
as gastric biopsy specimens as an alternative to existing methods. (Cerqueira et al, J Clin Microbiol, 2011). In collaboration with the
groups of Maria J. Vieira, CEB, Universidade do Minho and Nuno Azevedo, FEUP, Porto.
Systematic characterization of the intronic portion of cadherin superfamily members and identification of intronic regions
constituting putative targets/triggers of regulation, using a bioinformatics approach and biological data mining
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We identified cadherin intronic-specific sites that may constitute novel targets/triggers of cadherin superfamily expression
regulation. These findings pinpoint the need to identify mechanisms affecting particularly MIR and MaLR elements located in introns
2 and 3 of human cadherin genes, possibly important in the expression modulation of this superfamily in homeostasis and cancer.
(Oliveira P et al, EJHG, 2012). Collaboration with David Huntsman, BCCA, Vancouver, Canada; Elia Stupka, Milan, Italy; Remo Sanges,
Naples, Italy.
Identification of alternative E-cadherin transcripts encompassing starting exons within intron 2 and knowledge on the tissue
specificity and functionality, target effectors and associated signalling-pathways of at least one of them
We demonstrated, for the first time, the existence of novel transcripts starting within CDH1 intron 2 and, more importantly, we
discovered a new mechanism by which a novel E-cadherin isoform impairs the canonical E-cadherin function. We also found
evidences that this impairment is likely to occur through modulation of inflammatory machinery, providing additional clues for the
long recognized link between inflammation and cancer progression. We believe that this data encloses the potential for future novel
therapeutic approaches in epithelial cancers. (Pinheiro H et al, Submitted). Collaboration with David Huntsman, BCCA, Vancouver,
Canada; Elia Stupka, Milan, Italy; Remo Sanges, Naples, Italy; Peter Jordan, INSA, Lisbon, Portugal.
Molecular pathway leading to E-cadherin dysfunction involving miR-101 and EZH2 in gastric cancer
We profiled miRNAs’ expression in a series of primary gastric cancer cases and confirmed wide miR-101 downregulation. We
identified chromosomal deletions as the genetic cause for this downregulation in most cases and put together a cascade of events
starting with miR-101 loss, followed by EZH2 upregulation, culminating in E-cadherin function disruption, using an in vitro model.
Moreover, we were able to correlate all these steps in a series of well characterised primary gastric cancer cases, and associate this
pathway specifically with the intestinal type of gastric cancer. (Carvalho J et al, in press J Pathol 2012). Collaboration with Beatriz
Carvalho and Nicole C. van Grieken, VuMC, Amsterdam Holland; and Manuel Santos, University of Aveiro, Portugal.
E-Cadherin repressor molecules in gastric cancer and assessment of a possible correlation with E-Cadherin impairment
Three of these molecules MAPK14, FAM48A and Tcf3 are negative E-Cadherin modulators and were consistently overexpressed in
gastric tumours and thus may constitute prime candidates with a relevant role in the progression of gastric cancer. (Ferreira D et al,
in preparation). Collaboration with Beatriz Carvalho and Nicole C. van Grieken, VuMC, Amsterdam, Holland.
CDH1 germline mutations occur in less than 10% of the cases of gastric carcinoma patients younger than 50 years
We have previously documented that CDH1 germline mutations occur in early onset diffuse gastric cancer patients (EODGC) without
family history. However, the real frequency in this setting in stll not well established. We screened the entire coding region and exon
flanking sequences of the CDH1 gene was analysed by direct sequencing in 21 EODGC patients aged =50 years. The potential
deleterious nature for a new CDH1 missense variant was assessed by cell-cell aggregation and invasion assays. Somatic CDH1
mutation, loss of heterozygosity (LOH) and promoter hypermethylation was explored in the tumour from one CDH1 germline
mutation carrier. We found two novel CDH1 germline variants were identified in 21 EODGC cases, c.670C>T and -63C>A. Functional
analysis of the c.670C>T missense variant classified this mutation as non-pathogenic. The analysis of CDH1 somatic second hits failed
to demonstrate E-cadherin structural and epigenetic alterations in the tumour sample. Data from the present work and a systematic
review of the literature revealed that CDH1 germline mutations occurred in 7.2% of EOGC patients invariably with diffuse of mixed
histology. From these, proved CDH1 mutation pathogenicity has been assigned only to 2.3% of the cases who were recurrently
diagnosed before 35 years old.
In silico analysis of E-cadherin missense mutations show that loss of protein function is related to its destabilization
E-cadherin germline mutations are associated to high risk to develop Hereditary Diffuse Gastric Cancer (HDGC) and missense
mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to
loss-of-function, although the causal factor is unknown. We tested whether protein destabilization could account for the
pathogenicity of E-cadherin missense mutations in HDGC, using in silico and in vitro tools. FoldX algorithm was used to calculate the
impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by
SIFT. Interestingly, DGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death,
suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological
relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V,
S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits
shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by
stabilization with the artificial mutation L583I (structurally tolerated, when predicted by FoldX). We established for the first time that
an E-cadherin structural model is suitable to predict the impact of the majority of cancer-associated missense mutations and we
show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo.
HDGC: the importance of E-cadherin binding partners
We developed a novel and simplified method to unravel the pathogenic significance of E-cadherin missense mutations. We used cells
stably expressing WT E-cadherin and seven HDGC-associated mutations (five intracellular and two extracellular) and studied by
proximity ligation assays (PLA) how these mutants bind to key partners for E-cadherin trafficking and as a consequence, lead to Ecadherin deregulation and loss of function. We focused our attention on the interaction with fundamental regulators of E-cadherin
function and trafficking: p120, ß-catenin, PIPKI¿ and Hakai and showed that cytoplasmic E-cadherin mutations affect the interaction
of one or more binding partners compromising the stability of E-cadherin at the plasma membrane and likely affecting the
competence of the adhesion complex. In the present work, we demonstrated that the study of the interplay between E-cadherin and
its binding partners using PLA is an easy, rapid, quantitative and highly reproducible technique that can be applied in routine labs to
verify the pathogenicity of E-cadherin missense mutations for HDGC diagnosis, especially those located in the intracellular domain of
the protein.
New method to evaluate pathogenic significance of E-cadherin missense mutations associated to E-cadherin deficiency induces
Notch-dependent cell survival through upregulation of Bcl-2
We have previously shown that overexpression of mutant human E-cadherin in Drosophila produces a phenotype characteristic of
downregulated Notch. We studied whether Notch signalling could be influenced by E-cadherin. We verified that E-cadherin mutants
lose the ability to inhibit Notch-1 signalling when compared to wild-type E-cadherin cells. Further, Increased Notch-1 activity in Ecadherin-deficient cells correlated with increased expression of Bcl-2, and increased resistance to apoptotic stimuli. After Notch-1
inhibition, E-cadherin-deficient cells were re-sensitized to apoptosis in a similar degree to wild-type E-cadherin cells. We also show
19
that Notch-inhibiting drugs are able to significantly inhibit the growth of E-cadherin-deficient cells xenografted into nude mice. This
effect was comparable with the one observed in animals treated with the chemotherapeutic agent taxol, a chemical inducer of cell
death. In conclusion, our results show that aberrant Notch-1 activation, Bcl-2 overexpression and increased cell survival are likely to
play a crucial role in neoplastic transformation associated with E-cadherin impairment. These findings highlight the possibility of new
targeted therapeutical strategies for the treatment of tumours associated with E-cadherin inactivation.
ADP-ribosylation factor 6 and PIPKIgamma as key molecules in the recovery of E-cadherin expression by chemical chaperones
Previously, we found possible to restore in vitro mutant E-cadherin associated to HDGC syndrome by using Chemical Chaperones
(CCs). In the work we disclosed the molecular mechanisms underlying the CCs effects in E-cadherin regulation. Using cells stably
expressing WT E-cadherin or two HDGC-associated missense mutations, we show that upon DMSO treatment, not only mutant Ecadherin is restored and stabilized at the plasma membrane (PM), but also Arf6 and PIPKIgamma expressions are altered. We show
that modulation of Arf6 expression partially mimics the effect of CCs, suggesting that the cellular effects observed upon CCs
treatment are mediated by Arf6. Further, we show that E-cadherin expression recovery is specifically linked to Arf6 due to its role on
endocytosis and recycling pathways. Finally, we demonstrated that, as DMSO, several others CCs are able to modulate the trafficking
machinery through an Arf6 dependent mechanism. Interestingly, the more effective compounds in E-cadherin recovery to PM are
those that simultaneously inhibit Arf6 and stimulate PIPKIgamma expression and binding to E-cadherin. We presented the first
evidence of a direct influence of CCs in cellular trafficking machinery and showed that this effect is of crucial importance in the
context of juxtamembrane E-cadherin missense mutations associated to HDGC. We propose that this influence should be taken into
account when exploring the therapeutic potential of this type of chemicals in genetic diseases associated to protein-misfolding.
CPEB1 as a novel gene involved in gastric cancer with anti-angiogenic potential
Using the Drosophila model, we identified CPEB1 as a novel GC related gene. We showed that CPEB1 is downregulated in more than
90% of the primary gastric tumours analysed. We also found decreased CPEB1 levels in colorectal and breast cancer cell lines,
suggesting a broader implication of CPEB1 in cancer. Additionally, we present the first evidence for CPEB1’s silencing mechanism in
GC, through promoter methylation, particularly at a pivotal CPEB1 promoter CpG site. We uncovered CPEB1 anti-invasive role in
vitro. Additionally, by analysing the effect of CPEB1 overexpression in the chick CAM (chorioallantoic membrane assay) in the
formation of new blood vessels in the chick CAM (chorioallantoic membrane assay), we unravelled a new role for CPEB1 in
carcinogenesis, as a putative angiogenesis modulator and metastasis regulator. Accordingly, two main angiogenic effectors (VEGFA
and MMP14) were downregulated after CPEB1 overexpression. Additionally, we uncovered CPEB1 anti-invasive role in vitro.This
study has important clinical implications, not only in GC, but in many other types of cancer as likely affected by CPEB1 silencing, in
what concerns CPEB1’s value either as a tumour or as a prognostic marker. Our findings may also have an impact on GC therapeutics,
given that we have successfully reverted CPEB1 epigenetic inactivation by demethylating agents.
Establishment and validation of an in vitro model of TGFß1-induced EMT/MET to better understand the phenotypic and
transcriptional “reversible” switching of cancer cells during EMT/MET, with the ultimate goal of better understanding the
metastasis process
TGFß1 supply to spontaneously immortalized normal epithelial cells efficiently generated mesenchymal cells (M), and its removal
from the culture medium led to phenotypic reversion back to epithelia (MET). Cell population at these different stages potentially
reproduce the tumour heterogeneity so often described in primary and metastatic clinical samples. Further, supporting this view,
injection of E, M and TS cells in the tail vein of nude mice, induced a particularly lethal phenotype only for TS cells. These evidences
show that near-normal cells submitted to in vitro EMT/MET transitions acquire neoplastic features and constitute a useful cell model
system to study the metastatic process. (Oliveira P et al, in preparation). Collaboration with David Huntsman, BCCA, Vancouver,
Canada.
Whole transcriptome sequencing (RNAseq) of E, M and TS cells and bioinformatics analysis of the data
We generated a database that encompasses all differentially expressed genes and pathways that change along EMT/MET. The deep
bioinformatics analysis of this database has shown a large set of differentially expressed genes and biological pathways, many
related with cancer and metastases pathways. This data also supports the value of this model for the study of the metastatic process.
(Oliveira P et al, in preparation). Collaboration with David Huntsman, BCCA, Vancouver, Canada.
Analysis of the metabolic switches occurring during EMT/MET
We found that E and TS cells produce energy in an oxidative phosphorylation-dependent manner unlike M cells, which exhibited
lactate accumulation and oxidative phosphorylation shutdown. (Oliveira P et al, in preparation). Collaboration with Valdemar
Máximo and Jorge Lima, Cancer Biology Group, IPATIMUP, Porto, Portugal.
Alternative mechanisms of E-cadherin inactivation during EMT/MET
We showed a novel perspective over the regulation of E-cadherin function along EMT/MET, by demonstrating that E-cadherin
glycosylation with bisecting GlcNAc structures, catalysed by GnT-III enzyme, has major consequences in the regulation of its function
in the EMT/MET biological processes. Moreover, we have also provided compelling evidence of increased CpG island methylation at
the Mgat3 promoter, underlying the down regulation of Mgat3 expression in M cells. (Pinho SS and Oliveira P et al, PlosOne 2012).
Collaboration with Salomé Pinho and Celso Reis, Carcinogenesis Group, IPATIMUP, Porto, Portugal.
P-Cadherin expression mediates stem cell properties in basal-like breast cancer.
Using a series of breast cancer cell lines and primary tumours, we showed that P-cadherin was directly associated with the
expression of the breast stem markers CD44, CD49f and ALDH1 in the basal subtype. Moreover, cell populations enriched for Pcadherin expression comprised increased in vitro mammosphere forming efficiency and capacity to grow colonies in 3D cultures, as
well as greater tumourigenicity. Importantly, an association was found with stem/progenitor-like phenotypes of the breast, including
the luminal progenitor population, CD49f+CD24+. Additionally, P-cadherin expression conferred resistance to X-ray induced cell
death, sustaining a role for this molecule in another stem cell property. In summary, we demonstrated, for the first time, that Pcadherin mediates stem cell properties, which could be explored in order to better define the CSC phenotype of basal-like breast
tumours and the cell-of-origin of this malignancy. (Vieira et al. Stem Cells 2012)
This work has been developed in collaboration with Robert B. Clarke from Patterson Institute for Cancer Research, Manchester
University, UK.
P-cadherin promotes cancer cell invasion by interference with E-cadherin suppressor function.
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We aimed to investigate if P-cadherin expression would constitute a new mechanism to inactivate E-cadherin function in invasive
breast cancer cells. Using siRNAs, both cadherins were silenced, independently or simultaneously, in invasive E- and P-cadherin coexpressing breast cancer cells. Besides proving E-cadherin/P-cadherin proximity at the cell membrane, we showed that P-cadherin
promotes invasion by the disruption caused in the interaction between E-cadherin and cytoplasmic catenins. P-cadherin also induces
cell migration and survival, and the signalling pathways regulating these effects have been identified. Cadherins co-expression also
significantly enhances in vivo tumour growth. In humans, E- and P-cadherin co-expression was significantly correlated with highgrade and poor survival tumours, being an independent prognostic factor. (Ribeiro et al. FASEB J submitted)
This work has been developed in collaboration with Manuel Santos from Department of Biology and CESAM, University of Aveiro,
Portugal.
C/EBPbeta is a transcriptional regulator of the pro-invasive CDH3/P-cadherin gene in breast cancer cells
Recently, we described the existence of several C/EBPbeta transcription factors binding sites at the CDH3 promoter. The aim of this
study was to assess if the transcription factor C/EBPbeta was directly involved in the transcriptional activation of CDH3 gene in a
breast cancer cell model. We demonstrated that C/EBPbeta co-localizes with P-cadherin in breast cancer cells and functions as a
transcriptional regulator of CDH3/P-cadherin gene, directly interacting with distinct specific regions of the CDH3 promoter.
Interestingly, this transcriptional activation was only reflected at the P-cadherin protein levels concerning the LIP isoform. From this
study, we can conclude that CDH3/P-cadherin is a newly defined transcriptional target gene of C/EBPbeta in breast cancer, and the
important binding sites that are relevant for this activation to occur have been identified. (Albergaria et al. submitted)
Aberrant P-cadherin expression is associated with hypoxic/glycolytic and acid resistant phenotype in breast cancer
Hypoxia, and the consequent glycolytic and acid-resistant phenotypes, are associated with poor prognosis in breast cancer patients,
as well as are related with enhanced in vitro cancer cell invasion and migration. Similarly, we have identified that the aberrant
expression of the cell-cell adhesion molecule P-cadherin is a poor prognosis marker in breast cancer, and induces cancer cell invasion
and migration in vitro. In this work, we studied the association between P-cadherin overexpression and hypoxic/acidic-resistant and
glycolytic phenotype in a large series of 465 invasive breast carcinomas. P-cadherin overexpression was significantly and directly
associated with the expression of HIF1a, Glut1, CAIX, MCT1 and CD147. In addition, we found that P-cadherin silencing by siRNA in
BT20 and SUM149 breast cancer cells, reduces the expression of CAIX. Also transfection of P-cadherin cDNA, in MCF-7/AZ breast
cancer cells, is able to increase CAIX expression. These results suggest that aberrant P-cadherin expression in breast cancer cells is
associated with a hypoxic/acidic-resistant and glycolytic phenotype, which needs to be further explored. (Sousa et al. in preparation)
The bacterial protein azurin is a new candidate drug to treat P-cadherin overexpressing breast cancer
P-cadherin-overexpressing tumours show a highly aggressive clinical behaviour, due to metastasization and do not have until now a
targeted therapy. Azurin is a water-soluble protein, produced by Pseudomonas aeruginosa found to induce cytotoxicity towards
human cancer cells, in vitro and in vivo, mediated in part by a preferentially entrance into cancer cells compared to normal cells. It
also has a particular ability to mediate high-affinity interactions with unrelated proteins, conferring on it the property of a natural
scaffold for therapeutic purposes. Due to structural similarities between azurin and cadherins, we hypothesized that azurin could be
a scaffold against P-cadherin in breast cancer. SPR experiments revealed strong interactions between azurin and both P-and Ecadherins. In vitro, one single dose of azurin caused a specific decrease on P-cadherin protein levels from 30-50% in two different
breast cancer cell lines. On the other hand, the levels of E-cadherin, a known tumour suppressor, remain unaltered or even
increased. Additionally, the sP-cad was reduced after azurin treatment and Matrigel invasion assays demonstrated that azurin
reduces the invasive phenotype of the cells, concordant with the decrease on P-cadherin. We have also observed a decrease in
MMP2 activity in the extracellular media of azurin treated cells. Moreover, azurin led to a decrease in the phosphorylation levels of
both FAK and Src proteins, non-receptor tyrosine kinases activated by P-cadherin overexpression, involved in several signaling
pathways that regulate cell-cell and cell-matrix adhesion. Altogether, our data show that azurin exhibits a specific preference for Pcadherin, abrogating its invasive effects and, therefore, may have a potential use in the treatment of breast carcinomas
overexpressing this protein. (Bernardes et al. in preparation)
This work has been developed in collaboration with Arsénio Fialho from IBB/IST, Lisbon, Portugal.
1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter
demethylation
The triple-negative subgroup of breast cancer includes a cluster of tumors exhibiting low E-cadherin expression (metaplastic
carcinomas). In several cancer models, 1alpha,25-dihydroxyvitamin D3 (1a,25(OH)2D3) induces differentiation by increasing Ecadherin expression. The Vitamin D receptor (VDR) was evaluated as a possible therapeutic target for metaplastic carcinomas and
1a,25(OH)2D3 effects as a differentiating agent in triple-negative breast cancer cells were assessed. We found that most of the
metaplastic carcinomas were positive for VDR expression. Furthermore, 1a,25(OH)2D3 promoted differentiation of MDA-MB-231
cells by inducing de novo E-cadherin expression, an effect that was time- and dose-dependent. Also, E-cadherin expression was due
to promoter demethylation. Thus, metaplastic carcinomas may respond to 1a,25(OH)2D3, since they express VDR and 1a,25(OH)2D3
induces de novo E-cadherin expression in breast cancer cells by promoter demethylation. (Lopes et al. Anticancer Research, 2012)
The breast cancer stem cell markers CD44+CD24-/low and ALDH1high identify cancer stem cells with distinct levels of
differentiation.
We studied the distribution of the breast cancer stem cell markers CD44, CD24 and ALDH1 in a series of 466 invasive breast
carcinomas and eight breast cancer cell lines, from distinct intrinsic breast cancer subtypes. We found, however, that the overlap
between CD44+CD24-/low and ALDH1high CSC phenotypes were very small, as well as their distribution among intrinsic breast
cancer subtypes. Due to this discrepancy, it is imperative to improve the methods and biomarkers that identify breast CSCs within
the distinct molecular subtypes, because it is pivotal to translate the CSC concept to the clinical practice. In the future, the
recognition of reliable markers to distinguish the CSC pool in each molecular subtype will be decisive for the development of specific
target therapies. (Ricardo et al. J Clin Pathol 2011)
This work has been developed in collaboration with Jorge F. Cameselle-Teijeiro from Complexo Hospitalar Universitario de Vigo
(CHUVI), Spain.
The Nottingham Prognostic Index is a reliable prognostic tool also in triple-negative breast cancers
The Nottingham Prognostic Index has been shown to accurately predict patient outcome in stratified groups with a follow-up period
of 15 years after primary diagnosis of breast cancer. However, there are conflicting results on the prevalence of lymph node
21
metastasis at the time of diagnosis in triple-negative breast cancer (TNBC) patients, but it is currently accepted that triple-negative
breast cancer does not metastasize to axillary nodes and bones as frequently as the non-triple-negative carcinomas, favouring
instead, a preferentially haematogenous spread. Hypothetically, this particular tumour dissemination pattern would impair the
reliability of using Nottingham Prognostic Index as a tool for triple-negative breast cancer prognostication.
The present study tested the effectiveness of the Nottingham Prognostic Index in stratifying breast cancer patients of different
subtypes with special emphasis in a triple-negative breast cancer patient subset versus non- triple-negative breast cancer. We
demonstrated that, besides the fact that TNBC disseminate to axillary lymph nodes as frequently as luminal or HER2 tumours, we
also showed that TNBC are larger in size compared with other subtypes and almost all grade 3. The importance of this study relies on
the need of prognostication improvements on TNBC, showing, at a clinical standpoint, that Nottingham Prognostic Index is as a
truthful prognostic tool in TNBC. (Albergaria et al. BMC Cancer 2011)
The immunohistochemical evaluation of CLDN3, CLDN4 and CLDN7 is insufficient to identify the CLDN-low molecular subtype of
breast carcinomas
The recently characterized CLDN-low molecular subgroup of breast tumours increased the interest in these molecules. Our aim was
to explore the pattern of expression of CLDNs among a large series of invasive breast carcinomas and analysed the correlation
between the combinatorial expression of CLDN3/CLDN4 and classical prognostic factors and biological markers. In addition, we also
compared the characteristics of tumours with low expression of CLDN3, CLDN4 and CLDN7, assessed by immunohistochemistry (IHC),
and the ones from CLDN-low subgroup of tumours previously defined by genomic assays. The combinatorial analysis of the
expression of CLDN3/CLDN4 showed a significant association between high CLDN3/CLDN4 levels and triple-negative tumours, as well
as with a worse patient outcome. This combined analysis may provide useful information for breast carcinomas, since these two
CLDN members are putative therapeutic targets. Comparing tumours with low expression of CLDN3, CLDN4 and CLDN7 with tumours
previously referred as CLDN-low by genomic assays, we demonstrated that the evaluation of these three specific CLDNs is insufficient
to identify the CLDN-low molecular subtype of breast tumours. The analysis of several other molecular markers, such as EMT
markers, should be probably added to improve the identification of this subgroup of tumours by IHC, which seems be most likely
enriched in carcinomas with metaplastic differentiation. (Ricardo et al. Histol & Histopathol, 2012 in press)
This work has been developed in collaboration with Jorge F. Cameselle-Teijeiro from Complexo Hospitalar Universitario de Vigo
(CHUVI), Spain.
Metaplastic breast carcinomas have similar features to the ones included in the claudin-low molecular subtype
The claudin-low molecular subtype of breast cancer includes triple negative invasive carcinomas, with a high frequency of
metaplastic and medullary features. The aim of this study was to evaluate the immunohistochemistry expression of claudins in a
series of metaplastic breast carcinomas. We also assessed other claudin-low features, such as the cancer stem cell-like and epithelialto-mesenchymal transition phenotypes. The negative/low expression of claudins and E-cadherin, high levels of vimentin, and the
breast cancer stem cell phenotype suggests that metaplastic breast carcinomas have similar features to the ones included in the
claudin-low molecular subtype, specially their mesenchymal components. (Gerhard et al. The Breast, 2012 in press)
There is a concordance of molecular phenotypes between in situ and invasive components of breast carcinomas
The current system of pathologic classification of human breast cancers does not take into account the biologic determinants of
prognosis, nor is there a consensus regarding the progression from in situ to invasive carcinoma. This study compared the molecular
phenotypes of in situ and invasive components of breast cancer in the same sample. The overall concordance on the molecular
phenotypes between in situ and invasive components was 94%, supporting the theory of parallel disease in breast tumorigenesis.
(Martins et al. Hum Pathol, 2011)
OSNA assay (to evaluate CK19 expression) can be used in all breast cancer cases with a potential low rate of false negative for
detection of micrometastasis
The sentinel lymph node (SLN) is the first lymph node to receive the lymphatic drainage of a primary tumour; based on the
knowledge that CK19 is positive in more than 95% of breast carcinomas, a molecular method for intraoperative diagnosis of SLN
metastases (the one-step nucleic acid amplification (OSNA) assay) was developed.
Our aim was to evaluate CK19 immunoreactivity in a series of special histological types of breast carcinoma, in order to verify
whether the OSNA assay can be used in all breast cancer cases independently of the histological type. We found that most breast
cancer cases were positive for CK19, independent of the histological type; therefore the OSNA assay can be used in all breast cancer
cases with a potential low rate of false negative for CK19 detection of micrometastasis. There is an important variation between the
positivity assessed on TMAs and the entire tissue; these findings can be clinically relevant because, in some cases, CK19 is evaluated
on core-needle biopsy prior to surgery. (Alvarenga et al. J Clin Pathol 2011)
Pattern of oncogenic mutations in gastric cancer with microsatellite instability
We determined the frequency of gene mutations in members of Mitogen-activated protein kinase (MAPK) cascade and
phosphatidylinositol 3-kinase (PI3K) survival pathways. Epithelial Growth Factor Receptor (EGFR), KRAS, BRAF, PIK3CA and MLK3
mutations were screened in a series of 63 gastric carcinomas with high levels of microsatellite instability (MSI). In selected tumour
cases, EGFR expression was evaluated by immunohistochemistry. Association studies between molecular data and clinicopathologic
characteristics were performed. Mutations in EGFR (3'-untranslated region [UTR] polyA repeat), KRAS, PIK3CA and MLK3 genes
occurred in 30 (47.6%), 11 (17.5%), 9 (14.3%) and 2 (3.2%) of the MSI gastric cancer (GC) cases, respectively. No BRAF or EGFR
hotspot mutations were identified. Overall, mutations in at least one of these genes were found in 55.6% (35/63) of gastric
carcinomas. From those mutant cases 40.0% (14/35) of them had concomitant gene mutations, always involving EGFR polyA
deletions. Interestingly, we observed significant associations between oncogenic mutations and female gender (p = 0.046) old age of
diagnosis (p = 0.001) and intestinal subtype (p = 0.043). Our results show that MSI gastric carcinoma frequently shows activation of
EGFR-MAPK and PI3K pathways. Within all alterations found, deletions of the A13 repeats of EGFR were common, suggesting this
molecular event as an important biomarker for stratification of GC patients for treatment with EGFR inhibitors.
MEK1/2 and PI3K inhibition differentially affects cell survival and death in CRC cell lines harboring distinct genetic alterations
To elucidate the potential benefit of targeting the MAPK and PI3K signalling pathways in CRC patients, we aimed at assessing the
cellular effects of MAPK and PI3K inhibition by siRNA technology, as a first approach, on proliferation and survival of CRC cells
harbouring genetic alterations in KRAS, BRAF and/or PIK3CA. Interestingly, CRC cell lines harboring distinct genetic alterations
responded differently to MEK1/2 and/or PIK3CA inhibition. Interestingly, PIK3CA was shown to be the most effective target. In
22
particular, downregulation of PI3Kp100a significantly decreased proliferation/viability of HCT116 and SW480 cells which harbor
mutations in KRAS/PIK3CA and KRAS, respectively. Furthermore, downregulation of PI3Kp100a significantly induced apoptosis in
HCT116 cells, but not in SW480, which is in contrast with the results obtained for cell cycle arrest in which downregulation of
PI3Kp100a promoted cell cycle arrest in SW480 but not in HCT116 cells. Additional studies are being performed to further elucidate
the underlying mechanisms. This study demonstrates that inhibition of MAPK and/or PI3K pathways could provide an alternative
approach to overcome therapy resistance in mCRC patients. The identification of novel therapeutic strategies will undoubtedly have
an impact in the clinical management and, eventually, on the overall survival rate of patients with mCRC.
Effects of mRNA mistranslation in normal cells, both at the molecular and cellular levels, to clarify whether mRNA mistranslation
is relevant in initiation and progression of cancer
We evaluated cell viability, proliferation, apoptosis and the ability for cell transformation of tRNAser mutant expressing cell lines. The
results show that all cell lines were equally viable and displayed similar apoptotic level and proliferation capacity when compared
with cells expressing the wild-type tRNA. Importantly, cells expressing the mutant tRNAser that misincorporate Alanine have
increased transforming (in vitro) and tumorigenic (in vivo) potential. These results demonstrate that mistranslation has a role in
cancer initiation. (Ongoing). Collaboration with Manuel Santos, University of Aveiro, Portugal.
Mistranslation level of two colon cancer cell lines and an immortalized normal human embryonic kidney cell line using a dualluciferase assay
Preliminary results have shown that 1/2 cell lines tested showed high level of translation errors comparing with the normal cell line
HEK293. These results demonstrate that mistranslation in maintained and likely selected for, throughout cancer progression.
(Ongoing). Collaboration with Manuel Santos, University of Aveiro, Portugal.
INTERNATIONALIZATION/NETWORKING
National collaborations
Alexandre Carmo, IBMC, Porto
Ana Paula Pêgo, INEB, Porto
Arsénio Fialho, IBB-Instituto Superior Técnico, Lisboa
Catarina Almeida, INEB, Porto, Portugal
Cristina Barrias, INEB, Porto, Portugal
Fátima Baltazar, ICVS, University of Minho, Braga
Fernando Magro, FMUP, Porto
Isabel Palmeirim, Department of Medicine, University of Algarve, Faro
Isabel Rocha, CEB, University of Minho, Braga
João Taborda Barata, IMM, FMUL, Lisboa
José Manuel Costa, INSA Ricardo Jorge, Porto
Manuel A. Santos, CESAM, University of Aveiro, Aveiro
Manuel Coimbra, University of Aveiro, Aveiro
Maria João Vieira, CEB, University of Minho, Braga
Maria Oliveira, INEB, Porto
Mário Dinis Ribeiro, FMUP, Porto
Mário Barbosa, INEB, Porto
Nuno Azevedo, FEUP, Porto
Nuno C. Santos, IMM, FMUL, Lisboa
Nuno Lunet, FMUP, Porto
Paulo Pereira, IBILI, Coimbra
Paulo Pereira, IBMC, Porto
Pedro Granja, INEB, Porto
Peter Jordan, INSA Ricardo Jorge, Lisboa
International collaborations
Australia
Amanda Charlton, Department of Pathology, the Children's Hospital at Westmead, Sydney
Georgia Chenevix-Trench, NHMRC Senior Principal Research Fellow, The Queensland Institute of Medical Research, Brisbane
Belgium
Marc Mareel, Laboratory of Experimental Cancer Research, Department of Radiotherapy and Nuclear Medicine, Ghent University
Hospital, Ghent
Marc Bracke, Laboratory of Experimental Cancer Research, Ghent University Hospital, Ghent
Brazil
Célia Carlini, Universidade Federal do Rio Grande do Sul, Porto Alegre
Dulciene Queiroz, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte
Rozany Dufloth, Faculdade de Medicina de Botucatu-UNESP
Canada
David Huntsman, British Columbia Cancer Agency, Vancouver
Chile
23
Paul Harris, Pontificia Universidad Católica de Chile, Santiago
Costa Rica
Vanessa Ramirez, Calderón Guardia Hospital, San José
Denmark
Lene J Rasmussen, University of Copenhagen, Copenhagen
Finland
Lauri A Aaltonen, Tumor Genomics Research Group, Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki
France
Alex Duval, INSERM, Hôpital Saint-Antoine, Paris
Eliette Touati, Institute Pasteur, Paris
Germany
Elisa Izaurralde, Max Plank Institute for Developmental Research, Tuebingen
Federico Canzian, German Cancer Research Center (DKFZ), Heidelberg
Sebastian Suerbaum, Hannover Medical School, Institute of Medical Microbiology and Hospital Epidemiology, Hannover
Thomas Meyer, Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin
Thomas Schulz, Institute of Virology, Medical School Hannover
Ireland
Dermot Kelleher, Department of Clinical Medicine, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin
Israel
Yosef Yarden, Weismann Institute, Rehovot
Italy
Elia Stupka, Milan, Italy
Franco Roviello, Dept Surgery and Oncology, University of Siena, Siena
Remo Sanges, Cluster in Biomedicine, Trieste
Peru
Robert Gilman, Department of Microbiology, Infection Disease Laboratory, Universidad Peruana Cayetano Heredia, Rimac, Lima
Spain
Carlos Gonzalez, Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (IDIBELL-ICO), Barcelona
Fernando Casares, Centro Andaluz de Biología del Desarrollo, Sevilla
Gabriel Capellá, Catalan Institute of Oncology (IDIBELL-ICO), Barcelona
Gema Moreno-Bueno, Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones
Biomédicas 'Alberto Sols' CSIC-UAM, Madrid
Jorge F. Cameselle-Teijeiro, Department of Pathology, Complexo Hospitalar Universitario de Vigo (CHUVI), Vigo
José Luis Skarmeta, Centro Andaluz de Biología del Desarrollo, Sevilla
José Palacios, Servicio de Anatomía Patológica, Hospital Virgen del Rocío, Sevilla
Luis Serrano, Systems Biology, CRG, Barcelona
Manel Esteller, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona
Sweden
Ola Söderberg, Department of Genetics and Pathology, University of Uppsala, Uppsala
The Netherlands
Bauke Ylstra, Microarray Core Facility (MAF) of the VU University Medical Center/ Cancer Center Amsterdam
Beatriz Carvalho, Dept Pathology, VU Univ. Medical Center, Amsterdam
Leen-Jan van Doorn, DDL Diagnostic Laboratory, Voorburg
Marjolijn Ligtenberg and Han van Krieken, Radboud University Nijmegen Medical Centre, Nijmegen
Nicole C. van Grieken, VuMC, Amsterdam
Robert Hofstra, Department of Medical Genetics, University of Groningen, Groningen
UK
Carlos Caldas, Cambridge Research Institute Li Ka Shing Centre, Cambridge
Göran Landberg, Paterson Institute for Cancer Research (PICR), University of Manchester, Manchester
Ian Sanderson, Institute of Cell and Molecular Science, Barts and The London, London
Jean Crabtree, St James' University Hospital, Leeds
John Atherton, University of Nottingham, Nottingham
Jorge Sérgio Reis-Filho, Institute of Cancer Research, London
Robert B. Clarke, Paterson University of Manchester, Manchester
USA
David Mooney, Lab of Cell and Tissue Engineering, School of Engineering and Applied Sciences (SEAS), Harvard University, Cambridge
Gregory Lauwers, Department of Pathology, General Hospital, Boston
Kevin Haigis, Molecular Pathology Unit of the Massachusetts General Hospital, Boston
24
FUTURE RESEARCH
To understand whether genetic diversity related to the polymorphic regions in H. pylori vacA intermediate-region and dupA plays a
role in gastric carcinoma development
To uncover novel regulatory sequences/factors/mechanisms responsible for E-cadherin expression and function impairment in
tumour initiation and
To better understand the pathogenesis of H. pylori infection by dissecting the molecular mechanisms underlying H. pylori-mediated
tight junction disturbance
To study of molecular basis and molecular mechanisms involved in the metastatic process through the application of our in vitro
model EMT/MET to cancer lines in 3D cultures and inoculation/injection in nude mice
To disclose why mRNA mistranslation is relevant for initiation and progression of cancer and drug resistance, using in vitro and in
vivo models
To evaluate how E-cadherin mutations are reflected in terms of integrin re-engagement
To identify a gastric-specific gene expression programme that may underlie the spectrum of tumours in HDGC
To determine the pathogenic relevance of germline missense mutations in HDGC carriers
To identify new strategies for colorectal cancer therapy using a MAPK- and PI3K-targeted approach
To disclose the regulatory molecular mechanism that modulates P-cadherin expression in normal epithelial tissues and to find
whether this mechanism is disturbed in cancer cells with de novo P-cadherin expression
To demonstrate, in vitro and in vivo, that P-cadherin expression is an alternative mechanism by which E-cadherin dysfunction occurs
in epithelial tumours and to identify P-cadherin-related downstream target effectors and associated gene networks
To evaluate which is the role of cancer stem cells and neural stem cells in the establishment of breast cancer brain metastases and if
there is a crosstalk between these two cellular entities in this setting
To understand if P-cadherin overexpression in breast carcinomas is a response to the low oxygen levels in the tumour
microenvironment, or is associated to the mitochondrial dysfunction, serving as a cancer cell survival signal
To study the in vivo effects of azurin and the expression profile and signalling pathways associated with the azurin treatment of Pcadherin overexpressing cancer cells
PARTICIPATION IN PHD PROGRAMS

Céu Figueiredo. Oncobiology module. Programa Graduado em Áreas da Biologia Básica e Aplicada (GABBA) da
Universidade do Porto.

Fátima Carneiro. Doctoral Programme for Physicians (Fundações Calouste Gulbenkian e Champalimaud). Participação no
Módulo de Oncobiology.

Fátima Carneiro. Programa de Doutoramento em Medicina e Oncologia Molecular: Coordenação e participação do/no
Módulo de Oncobiologia .

Fátima Carneiro. Programa de Doutoramento do IMM. Participação no nanocourse sobre Biology of Cancer.

Fátima Carneiro. Programa GABBA: Participação no Módulo de Oncobiologia.

Fernando Schmitt. GABBA (Graduate Program in Areas of Basic and Applied Biology), at IPATIMUP, Porto, Portugal.

Fernando Schmitt. Gulbenkian PhD Oncobiology module, Program of Advanced Medical Formation, with Champalimaud
Foundation participation, at IPATIMUP, Porto, Portugal.

Fernando Schmitt. Oncobiology module, Programa Doutoral de Medicina e Oncologia Molecular, Medical Faculty of Porto
University, at IPATIMUP, Porto, Portugal.

Fernando Schmitt. Oncobiology module, Programa Doutoral em Patologia e Genética Molecular do Instituto de Ciências
Biomédicas Abel Salazar, at IPATIMUP, Porto, Portugal.

Joana Paredes. Oncobiology module, GABBA (Graduate Program in Areas of Basic and Applied Biology) PhD Program, at
IPATIMUP, Porto, Portugal.

Joana Paredes. Oncobiology module, Gulbenkian-Champalimaud PhD Program of Advanced Medical Formation, at
IPATIMUP, Porto, Portugal.

Joana Paredes. Stem cells and Regenerative Cellular Therapies module, Biomedical Bioengineering PhD Program, at
Faculty of Engineering of Porto University, Porto, Portugal

José C. Machado. Oncobiology module, Programa Doutoral de Medicina e Oncologia Molecular, Medical Faculty of Porto
University, at IPATIMUP, Porto, Portugal.

José C. Machado. Oncobiology module. Programa Graduado em Áreas da Biologia Básica e Aplicada (GABBA) da

Patricia Oliveira. Module of Oncobiology to students from the Gulbenkian PhD Program for Medical Doctors.
PARTICIPATION IN MASTER PROGRAMS

Fátima Carneiro. Master de Oncologica Molecular do Centro Nacional de Investigaciones Oncológicas (CNIO). (Tema:
Cancer gástrico: dianas moleculares y modificadores biológicos; Madrid, 18 de Abril de 2010).

Fátima Carneiro. Módulo de Oncobiologia do Mestrado em Medicina Molecular da Faculdade de Medicina da
25

Joana Paredes. “Stem Cells: their association with cancer”, “Signalling, gene expression and post-transcriptional
regulation” module, Master Program in Molecular Genetics, at Biology Department of Minho University.

Joana Paredes. “Breast Cancer Stem Cells: its importance in cancer biology”, Stem cells and Regenerative Cellular
Therapies module, Master in Bioengineering, at Faculty of Engineering of Porto University, Porto, Portugal

Joana Paredes. “Breast Cancer”, Master course in Medicine, Algarve University.

Joana Paredes. “Cancer Stem Cells: implications for cancer biology and therapy”, Advanced Course in Oncobiology, faculty
of Medicine of Coimbra University.

José Carlos Machado. Módulo de Oncobiologia do Mestrado em Medicina Molecular da Faculdade de Medicina da

Raquel Seruca“E-cadherin and diffuse gastric cancer”, Advanced Course in Oncobiology, faculty of Medicine of Coimbra
University.
PRIZES

Ângela M. Costa. FEBS Bursary 36th FEBS Congress Biochemistry for Tomorrow’s Medicine, Turin, Italy, June 2011

Daniel Ferreira. EMBO Short-Term Fellowship Project “Systematic analysis of novel and previously characterized ECadherin expression repressors/modulators in gastric cancer” to be performed at Beatriz Carvalho’s lab (VuMC,
Amsterdam, Holland)

Fernando Schmitt. Educator of the Year 2011Papanicolaou Society of Cytology, USA

Joana Carvalho. Keystone Symposia travel scholarship “Mechanism and Biology of Silencing” Meeting, Monterey,
California, March 2011

Joana Carvalho. Poster award finalist European Society of Human Genetics Conference 2011, Amsterdam, The
Netherlands, May-June 2011

Joana Paredes. Premio Centro Oncológico de Galicia “José Antonio Quiroga y Piñeyro” Real Academia de Medicina e
Cirugia de Galicia, A Coruña, Spain

Patrícia Oliveira. EMBO Short-Term Fellowship Project “The identification and description of novel regulatory mechanisms
affecting the expression of cadherin gene superfamily during development and cancer" to be performed at José Luis
Gómez-Skarmeta’s lab (CABD, Seville, Spain)

Renata Carriço. FEBS Bursary36th FEBS Congress Biochemistry for Tomorrow’s Medicine, Turin, Italy, June 2011

Rui M. Ferreira. FEBS Bursary 36th FEBS Congress Biochemistry for Tomorrow’s Medicine, Turin, Italy, June 2011
INVITED TALKS

Carla Oliveira . “E-cadherin the sticky component of epithelial tissues: old gene new stories”. CEDOC. Lisbon, Portugal.
May 2011.

Carla Oliveira. “Regulation of E-cadherin expression and function in cancer”. BIOCANT. Coimbra, Portugal. May 2011.

Carla Oliveira. “Tumor cell invasion and metastasis.". I Workshop on Cancer Research: biological and molecular basis.
Porto, Portugal. May 2011.

Céu Figueiredo. "Caracterização da virulência de Helicobacter pylori: uma oportunidade para identificar indivíduos com
maior risco de carcinoma gástrico?". Centro de Biotecnologia da Universidade Federal do Rio Grande do Sul. Porto Alegre,
Brazil. Dec 2011.

Céu Figueiredo. “Clinical relevance of Helicobacter pylori genotyping". Departament of Medical Biochemistry and
Biophysics Umea University. Sweden. Sept 2011.

Fátima Carneiro. "Càncer gàstric esporàdic i familiar". Societat catalana d’Anatomia patològica e Acadèmia de ciències
Mèdiques i de la Salut de Catalunya i de Balears. Barcelona. Feb 2011 .

Fernando Schmitt. “Slide seminar Breast Cytology”. 2nd SGH Breast Pathology Course. Singapura. 2011.

Fernando Schmitt. "Slide seminar “Unusual breast lesions". 100th USCAP Annual Meeting. San Antonio, USA. 2011.

Fernando Schmitt. “Slide seminar Molecular diagnostics and immunohistochemistry”. 6th Central European Regional
Meeting- Cytopathology. Balatonfured, Hungry. . 2011.

Fernando Schmitt. “Tumoral angiogenesis , GIST – Challenging the future". Curia Meeting. Curia, Portugal. . 2011.

Fernando Schmitt. “Seminario de Casos de Citologia”. VII Congrés Català de Citopatologia. St. Fruitós de Bages, Barcelona,
Spain. 2011.

Fernando Schmitt. “The use of immunocytochemistry in everyday practice”. 6th CE Regional Meeting . Cytopathology,
Balatonfured, Hungry. 2011.

Fernando Schmitt. “Vias de sinalização celular e novos tratamentos em Oncologia”. Sessão Inovação em Oncologia.
Lisboa, Portugal. 2011.

Fernando Schmitt. "Breast cancer-therapeutic targets and molecular classification”. International CME in Pathology.
Histopathology and Cytopathology Goa Medical College, Goa, India. 2011.

Joana Paredes. "P-cadherin in breast cancer: how invasion relates with cancer stem cells?". 1st Advanced Summer School
- Interrogations at the Biointerface – The Cancer/Regeneration Interface. Biblioteca Almeida Garret, Jardins do Palácio de
Cristal, Porto, Portugal. 2011.

Joana Paredes. "P-cadherin: a marker to identify and isolate cancer stem cells in basal-like breast cancer". 2nd I3S
Scientific Retreat – IBMC/INEB/IPATIMUP. Póvoa de Varzim, Portugal. . 2011.
26

Joana Paredes. “Alvos moleculares na terapia do cancro da mama”. III Conferências em Microbiologia e Biologia do
Cancro. Anfiteatro FFUP, Porto, Portugal. 2011.

Joana Paredes. “Células Estaminais no Cancro da Mama – Citopatologia”. XII Congresso Técnico de Anatomia Patológica.
Centro Multimeios de Espinho, Espinho, Portugal. 2011.

Joana Paredes. “Células Estaminais no Cancro da Mama”. 1º Encontro de Biologia Molecular em Saúde. Escola Superior
de Saúde Egas Moniz, Monte de Caparica, Portugal. 2011.

Joana Paredes. “Células Estaminais no Cancro da Mama”. Actualizações em Oncologia 2011. Auditório dos Hospitais da
Universidade de Coimbra, Coimbra, Portugal. 2011.

Joana Paredes. “Identificación de Células Madre en el Cáncer de Mama”. Prémio “Fundación Centro Oncológico de Galicia
José Antonio Quiroga Piñeyro” “Estudio de la evolución del cáncer de mama en el área de Vigo durante los últimos 36
años (1974-2009)”. Vigo, Spain. 2011.

Joana Paredes. “P-cadherin in breast cancer: is it a good therapeutic target to treat this disease?”. CEBAL Meeting. CEBAL
- Centro de Biotecnologia do Alentejo, Beja, Portugal. 2011.

Joana Paredes. “P-cadherin in Breast Cancer: the relatioship between cancer stem cells and invasion”. 5th Annual Meeting
on Cell Signallig – SINAL 2011. BIOCANT, Cantanhede, Portugal. 2011.

Joana Paredes. “P-cadherin in Breast Cancer: the relatioship between cancer stem cells and invasion”. 6th Intenational
Meeting of the Portuguese Society for Stem Cells and Cell Therapies (SPCE-TC). BIOCANT, Cantanhede, Portugal. 2011.

Joana Paredes. "P-cadherin: a novel therapeutic target in breast cancer”. IPO Meeting. Instituto Português de Oncologia
do Porto Francisco Gentil, Porto, Portugal. 2011.

Joana Paredes. “Tumor cell invasion and metastasis”. I Workshop on Cancer Research – biological and molecular basis.
IPATIMUP, Porto, Portugal. 2011.

José C. Machado. Should H. pylori screening and treatment of asymptomatic persons from high-risk populations be
promoted in Africa and Middle East to prevent gastric cancer? . 3rd Congress of the African Middle Eastern Digestive
Cancer Alliance. Rabat, Marrocos. Feb 2011.

Machado JC. Biomarcadores no CCRm. 5º Simpósio Nacional EGFR. . Cascais, Portugal. Feb 2011.

José C. Machado. Gastric carcinogenesis: is there a role for genetic susceptibility? . 17th Annual Meeting of the Japanese
Society for Helicobacter. Toyama, Japão. Jun 2011.

José C. Machado. Da molécula ao medicamento. Simpósio APIFARMA . Porto, Portugal. Jun 2011.

José C. Machado. EGFR signalling and gastric cancer. XXIVthInternational Workshop on Helicobacter and related bacteria
in chronic digestive inflammation and gastric cancer. . Dublin, Irlanda. Set 2011.

José C. Machado. Instabilidade de microssatélites. Qual a sua importância? . 7º Simpósio Nacional e Cancro Digestivo.
Albufeira, Portugal. Out 2011.

José C. Machado. Marcadores moleculares no cancro do pulmão: O ponto de vista laboratorial. Reunião da Comissão de
Pneumologia Oncológica. Monte Real, Portugal. Nov 2011.

José C. Machado. Carcinoma gástrico difuso: De Napoleão à perda de adesão e finalmente à imortalidade. III Conferências
Microbiologia e Biologia do Cancro. Porto, Portugal. Nov 2011.

Fernando Schmitt. "Breast Cytology: Can This Simple Diagnostic Test Provide Sophisticated Answers?". Theoreticalpractical course on non-gynecological cytology. Barcelona, Spain. 2011.

Fernando Schmitt. "Current trends in Breast Cancer”. A joint meeting between APTAP and UK NEQAS to celebrate 25
years. Carcavelos, Portugal. 2011.

Fernando Schmitt. "Cytology and Lung Cancer: Role in Diagnosis and Therapeutic Guidance" . Theoretical-practical course
on non-gynecological cytology. Barcelona, Spain. 2011.

Fernando Schmitt. "Lung Cytology”, International CME in Pathology". Histopathology and Cytopathology Goa Medical
College. Goa, India. 2011.

Fernando Schmitt. "Molecular Cytopathology”, International CME in Pathology . Histopathology and Cytopathology Goa
Medical College. Goa, India. 2011.

Fernando Schmitt. "Professional Expert Course HER2 Testing in Gastric Cancer". Kassel Meeting. Germany. 2011.

Fernando Schmitt. "Slide seminar Breast FNA". Theoretical-practical course on non-gynecological cytology. Barcelona,
Spain. 2011.

Fernando Schmitt. "Soft tissues FNA: Practical issues". Theoretical-practical course on non-gynecological cytology.
Barcelona, Spain. 2011.

Fernando Schmitt. “A Importância de um Programa de Controlo de Qualidade no laboratório de AP – Resultados Finais do
Estudo RETESTE”. XIII Jornadas de Senologia. Viseu, Portugal. 2011.

Fernando Schmitt. “Aplicação de técnicas moleculares em citologia”. XXVIII Congresso Brasileiro de Patologia e Congresso
Latinoamericano de Patologia. Maceió, Brasil. 2011.

Fernando Schmitt. “Cáncer de Mama: Grado de diferenciación en índice proliferativo o firma génica?”. XVII Reunión
Nacional de la Sección de Patología Mamaria. Vigo, Spain. 2011.

Fernando Schmitt. “Câncer de Mama: Grau histológico e indice proliferativo ou assinatura gênica?”. XVI Congresso
Brasileiro de Mastologia. Goiânia, Brasil. 2011.

Fernando Schmitt. “Carcinoma mamário triplo negativo”. Hospital Araújo Jorge da Associação de Combate ao Câncer em
Goiás. Goiânia, Brasil. 2011.

Fernando Schmitt. “Carcinomas metaplásticos da mama”. XXVIII Congresso Brasileiro de Patologia e Congresso
Latinoamericano de Patologia. Maceió, Brasil. 2011.
27

Fernando Schmitt. “Citopatologia Molecular”. VII Congrés Català de Citopatologia. St. Fruitós de Bages, Barcelona, Spain.
2011.

Fernando Schmitt. “From the cells to the molecules. An overview of molecular applications on cytology”. 7th Asia Pacific
IAP Congress. Taipei , Taiwan. 2011.

Fernando Schmitt. “How to set up a FNA clinic” and “Fine needle aspiration of breast”. Post-Congress Educational Courses
of the ESP. St. Petersburg, Russia. 2011.

Fernando Schmitt. Fernando Schmitt . “Signaling pathways as a target for cancer treatment” . “Identification of genomic
mutations in thyroid FNBA”. 8th Multidisciplinary Course on Thyroid Pathology and Cytology. Advanced Drug Delivery
Solutions for Cancer Therapy, Pharmaceutica Faculty of Porto University. Roma, Italy. Porto, Portugal. 2011.2011.

Fernando Schmitt. “Molecular Diagnosis in Breast Cytology”. Winter Meeting of Belgian Society of Clinical Cytology.
Brussels, Belgium. 2011.

Fernando Schmitt. “Morphological aspects of breast carcinoma on breast FNAB”, “Morphological aspects of epithelial
proliferative and papillary lesions on breast FNAB” and “Breast cytology – molecular classification and therapeutic
targets”. Fine needle aspiration cytology for practicing cytopathologists course. University and Regional Laboratories
Region Skane, Lund, Sweden. 2011.

Fernando Schmitt. “National investigation – preliminary results from the Re-Testing Study”. Personalized Healthcare in
Oncology. Lisbon, Portugal. 2011.

Fernando Schmitt. “Nuevos horizontes en la Baaf de Cáncer Mama”. XVI Congresso Latinoamericano. Lima, Peru. 2011.

Fernando Schmitt. “One size does not fit all! Finding therapeutic targets for subgroups of breast cancers” and “Drug
Resistance in Cancer: from biology to molecular target and drugs”. XX Porto Cancer Meeting . Porto, Portugal. 2011.

Fernando Schmitt. “P-Caderina no Cancro da Mama: o percurso de uma investigação”. XIII Jornadas de Senologia. Viseu,
Portugal. 2011.

Fernando Schmitt. “Resident’s Puzzle- Interactive Session ”. 36th European Congress of Cytology. Istanbul, Turquia. 2011.

Fernando Schmitt. “Pruebas Moleculares en Citologia”. XVI Congresso Latinoamericano. Lima, Peru. 2011.

Fernando Schmitt. “Seminar Speaker for Hong Kong Society of Cytology in the Year 2011”. Hong Kong Society of Cytology
Year 2011. Hong Kong, China. 2011.

Raquel Seruca. “Cancro gastrico in era moderna: dalla classificazione istopatologica alla classificazione molecolare”.
Update In Tema Di Anatomia Patologica E Ricaduta” CLINICA. Sorrento, Italy. May 2011.

Raquel Seruca. "E-cadherin a major culprit in invasion: Gastric cancer as model". Advanced Summer Schools Interrogations at the Biointerface. Porto, Portugal. June 2011.

José C. Machado. Diagnóstico Genético en Cardiologia. Perspectiva Clínica. I Jornada de Diagnóstico Genético en
Cardiologia. Madrid, Espanha. Dec 2011.
ORAL PRESENTATIONS

Nair Lopes. 1alpha,25-dihydroxyvitamin D3 induces the de novo expression of E-cadherin in MDA-MB-231 breast cancer
cells. 4th International Symposium Vitamin D and Analogs in Cancer Prevention and Therapy. Homburg, Germany. 2011.

Ferreira Santos L, Pereira T, Rodrigues B, Correia E, Moreira D, Vidinha J, Nunes L, Costa S, Machado JC, Castedo S,
Henriques C, Matos A, Oliveira Santos. Is there a Signal-Averaged ECG phenotype in patients with Brugada Syndrome? .
CardioRhythym. Hong Kong, China. 2011.

Patrícia Oliveira, Joana Carvalho, Mafalda Azevedo, Ali Heravi-Moussavi, Daniel Ferreira, Angela Burleigh, Calvin Roskelley,
Elia Stupka, Raquel Seruca, David Huntsman and Carla Oliveira. Uncovering RNA-signatures underlying EpithelialMesenchymal transition and Mesenchymal-Epithelial transition. 15th Annual GABBA Scientific Meeting, IBMC. Porto,
Portugal. 2011.

Patrícia Oliveira, Raquel Seruca, David Huntsman and Carla Oliveira. Uncovering RNA-signatures underlying EMT and MET:
targeting metastization. I3S Scientific Retreat. Póvoa de Varzim, Portugal. 2011.

Pereira T, Ferreira Santos L, Rodrigues B, Correia E, Moreira D, Nunes L, Costa S, Machado JC, Castedo S, Oliveira Santos.
Reproducibility of the signal-averaged ECG in a family screened for Brugada syndrome. CardioRhythym. Hong Kong, China.
2011.

Cirnes L, Fernandes R, Pina MJ, Ribeiro C, Sousa S, Machado JC. Caracterização das mutações do gene KRAS em doentes
com carcinoma do cólon e recto metastático e do gene EGFR em carcinoma do pulmão metastático. Encontros da
primavera em Oncologia. Évora, Portugal. 2011.

Costa JL, Sousa S, Fernandes R, Cirnes L, Machado JC. Non-optival massive parallel sequencing of BRCA1 and BRCA2 genes:
towards the diagnostic setting. 15ª Reunião Anual da SPGH. Lisboa, Portugal. 2011.
28
POPULATION GENETICS
OBJECTIVES
The group aims at understanding the origin and evolution of genetic diversity, their consequences and applications, both normal and
pathological, using autosomal, X and Y linked, and mtDNA markers.
In order to achieve the genetic characterisation of normal populations, their origins, phylogeny and evolution, and disease
susceptibility profiles, we develop descriptive and analytical formal tools and techniques adequate to specific genomic segments.
The applied research areas in which we concentrate our efforts are molecular diagnostics and forensics. Some of specific lines
currently pursued are: (a) the history, conservation and management of domesticates and laboratory animals (b) food quality
assessment, and (c) identification and diagnostic tools for humans, their commensal/pathogenic species, domesticates and
laboratory animals.
MAIN ACHIEVEMENTS
Genetic profiling of populations through autosomal markers
Argentinean population was characterized using a panel of InDels and SNPS polymorphisms providing a database suitable for
searches limited to ancient and/or degraded samples.
An autosomal STR portrait of the Libyan population was produced, adding relevant information to the complex genetic mosaic of
North Africa.
Genetic profiling of populations from the perspective of haplodiploid markers
X-chromosome microsatellites (STRs) were used to characterize Western Iberia populations (Portuguese and Galician, which were
indistinguishable, and showed a typical European pattern. The same kind of markers was used to characterize Colombians,
Greenlanders, Danes and Somalis.
Somali and Iraqi populations were characterized using a panel of X-chromosome Indels.
A panel of 25 X-chromosome SNPs was used to profile African (Angola, Mozambique) and Asian (Taiwan, China, Bangladesh)
populations: clear genetic differentiation between Sub-Saharan populations and those from northern Africa and the Mediterranean
was found, as well as between eastern and southern Africa (but not between Angola and Mozambique). Asian samples formed a
separate cluster with Bangladesh significantly different from both China and Taiwan.
Genetic profiling of populations from the perspective of female lineages
We have analyzed mtDNA sequences in the NE Portuguese Jewish community, detecting a remarkable signature of a Near East
ancestry, in accordance with our previous results for Y-chromosome.
Complete mitochondrial control sequences of Iberian Roma and previously published maternal lineages of other European Gysies
were analyzed and results show that the maternal lineage composition in the Roma groups follows a pattern of different migration
routes, with several founder effects, and low effective population sizes along their dispersal. Our data confirmed a North/West
migration route shared by Polish, Lithuanian and Iberian Roma. Eleven maternal founder lineages were identified and indicate the
Punjab state as the putative ancestral homeland of the European Roma.
In contrast with what was found for male lineages in Guinea-Bissau, female lineages of European origin are virtually absent, present
with a frequency above 10%, in accordance with the typical colonial gender-asymmetric pattern of admixture.
Genetic profiling of populations from the perspective of male lineages
The insertion/deletion polymorphisms at Y chromosome were investigated and its contribution to the establishment of phylogenies
assessed, concluding that although currently validated Indels are insufficient to establish a tree and to allow haplogroup assignment
in general, they are able to resolve some branches insufficiently defined by other markers.
Y chromosome microsatellites (STRs) were analyzed in Rondônia (Brazil) as well in Argentina (along with SNPs) contributing to the
clarification of the peopling of America and migrations, both pre- and-post Columbian.
The peopling of Europe and importance of the Neolithic contribution was also approached using Y chromosome and we conclude
that for some lineages, current data and tools are insufficient to satisfactorily infer time of origin and dispersion.
Using both STRs and SNPs we showed that in Guinea-Bissau, male lineages of European origin are present with a frequency above
10%.
Genetic databases and quality control developments
We participated in the GHEP-ISFG (Spanish and Portuguese Working Group of the International Society for Forensic Genetics)
Proficiency Test 2011, a paper challenge on evaluation of mitochondrial DNA results in forensic labs and collaborated in the
supervision and analysis of (a) the results of the Colombian interlaboratory Quality Control Exercise 2009–2010 and (b) the EDNAP
(the European DNA Profiling Group) Mitochondrial DNA Population Database (EMPOP).
Development of new genetic markers and techniques
A single base extension assay based on 15 diagnostic mtDNA SNPs able to differentiate Asian and European pig (Sus scrofa) maternal
lineages was developed. The test was robust, sensitive and accurate in a wide range of processed foodstuffs. The assay besides being
valuable for the control of Protected Denomination of Origin products is potentially useful for ancient DNA samples.
A panel of short amplicon SNP and Indel polymorphisms was developed with the purpose of typing highly degraded samples and
successfully tested in skeletal remains.
29
A 32 X chromosome Indel PCR multiplex system was developed. The set was applied to sub-Saharan African, European and East Asian
population samples, revealing high informative power and it was validated through segregation and mutation analysis in fathermother-daughters trios.
A multiplex PCR was developed allowing the rapid identification of Aspergillus fumigatus.
A novel subculture procedure for Aspergillus spp. resulted in several positive results that were not detected by the routine sampling
procedure.
Association of ATXN2 CAG repeat size with risk of amyotrophic lateral sclerosi
Ataxin 2 CAG long repeats are a risk factor for ALS and indicate a genetic link between spinocerebellar ataxia type 2 and ALS.
Formal and Statistical Genetics of X-chromosomal markers
A generalization of the IBD (identical-by-descent) approach created for autosomes was developed, allowing fast evaluation of their
usefulness in kinship assessment, particularly for pedigrees indistinguishable through autosomal markers.
Origin and spread of a common deletion causing mucolipidosis type II
Most of the mutations at GNPTAB are private, but c.3503_3504delTC is found detected among Israeli and Palestinian Arab-Muslim,
Turkish, Canadian, Italian, Portuguese, Irish traveller and US patients. We showed that it is associated with an haplotype, which origin
(~2063 years ago), is probably peri-Mediterranean.
The role of the Mannose-6-Phosphate pathway
The role of the M-6-P pathway in lysosomal function and dysfunction was reviewed, with special emphasis on storage disorders
associated to GlcNAc-1-phosphotransferase loss of function and evidencing alternative mechanisms to the M6P pathway for
lysosomal targeting.
Forensic use of insertion/deletion polymorphisms
We have demonstrated that in contrast to common belief, Indels perform poorly when the alleged father is a close relative of the
real father
Gene expression profile changes induced by azole antifungal drugs in Candida parapsilosis
Experimentally induced resistance to azole antifungal drugs was shown to be associated with increased expression of the
transcription factor MRR1, the major facilitator transporter MDR1, and several reductases and oxidoreductases. As in C. albicans,
upregulation of MRR1 and MDR1 is correlated with point mutations at MRR1 in the resistant strains. The resistant strain to
posaconazole showed upregulation of transcription factors UPC2 and NDT80 and increased expression of 13 genes involved in
ergosterol biosynthesis. Thus, tolerance to azoles seems to involve the activation of efflux pumps and/or increased ergosterol
synthesis.
Gains, losses and changes of function after gene duplication
Metallothioneins (MT) are proteins involved in heavy metal detoxification, protection against oxidative stress and cancer. Our
phylogenetic analyses of the mammalian family show that all four major genes originated through a single duplication event prior to
the radiation of mammals, but further expansion of MT1 gene has occurred in the primate lineage reaching in humans a total of 13
paralogs, 5 of which are pseudogenes mostly caused by the loss of invariant cysteines. MT1, MT2, and MT3 are ubiquitously
expressed while MT4 transcripts are present in brain, testes, esophagus and mainly in thymus. Two deleterious mutations (Cys30Tyr
and Arg31Trp) in MT4 with frequencies reaching about 30% in African and Asian populations suggesting the gene is inactive in some
individuals and physiological compensation for its loss must arise from a functional equivalent.
X chromosome inactivation in mouse
Human and mouse differ in the number and organization of the genes that escape inactivation; however we have established that
mouse escapees, like their human counterparts, can be clustered. Moreover, the fact that some non coding RNAs are not found on
the human X raises intriguing questions about potential regulatory roles of rapidly evolving ncRNAs.
Automated mtDNA sequence clustering and haplogroup assignment
A new strategy for mtDNA sequence clustering based on protein coding region analysis using a vectorization algorithm for a fast
calculation of similarities between sequences was developed. The method allows the automated assignment of sequences into major
haplogroups, avoiding the error-prone manual search of a phylogenetic tree and enables a quality control for sequences classified
manually.
Kinship estimation from genetic data
We have developed a simple method for estimating autosomal coancestry from genotypes using a linear regression method, using
average homozygosity as a proxy.
Evidence of intense gene flow between Iberian wild boars and South Iberian pig breeds
MtDNA analysis showed that pig husbandry in the Iberian Peninsula did not solely rely on imported Central European stock, but also
included the recruitment of local wild boars.
X-chromosome haplotype of Neandertal origin present among all non-African populations
We provided evidence for the presence of a Neandertal-derived X chromosome segment among all contemporary human
populations outside Africa, indicating a very early admixture between expanding modern humans and Neandertals prior to or very
early on the route of the out-of-Africa expansion.
Characterization of human ornithine transcarbamylase 3' untranslated regulatory region
We have shown that two major transcripts (OTC-t1 and OTC-t2) are more expressed than any other isoforms in all the tissues
analyzed, though a longer transcript (OTC-t3) was also isolated and characterized from the brain sample. We further demonstrated
that OTC-t1 and OTC-t2 transcripts display heterogeneity at the cleavage sites in a tissue-dependent manner.
The origin and evolution of overlapping genes
We have shown that human COG8 and PDF overlap is mediated by alterations in splicing and polyadenylation signals and - through a
comparative genomic survey - that the relative locations of these two genes have been changing over the last 445 million years from
distinct chromosomal locations in fish to overlapping in rodents and primates.
30

Thore Egeland. Norwegian University of Life Sciences, Department of Chemistry, Biotechnology and Food Science, Norway

Sónia Maciel. Agriculture Research Institute of Mozambique, Department of Animal Sciences, Artificial Insemination
Centre, Maputo, Mozambique

Miguel Fonseca. University of Vigo, Spain.

James Stewart . Max Planck Institute for Biology of Ageing, Cologne, Germany.

David Samuels . Vanderbilt University - School of Medicine (VUSM) Nashville, USA.

Johannes A. Lenstra. Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

Massimo Palmarini. Institute of Infection, Immunity and Inflammation College of Medical, Veterinary and Life Sciences .
University of Glasgow, Scotland (UK)

Anne W. Muiga. Jomo Kenyatta University of Agriculture and Technology. Nairobi, Kenya

Matt Hurles, Wellcome Trust Sanger Institute, UK. Genomics of male infertility

Don Conrad, Washington University School of Medicine, MO, USA. Genomics of male infertility

Laura Carrel, Penn State University USA. X- inactivation in Mus musculus

Michael E. Pfrender. Daphnia Genomics Consortium. Director Genomics Core Facility and Associate Professor in the
Department of Biological Sciences, University of Notre Dame, Indiana, USA.

Elizeu Carvalho. Univ.Estadual Rio Janeiro. Research on population genetics, forensics and biodiversity

Spanish and Portuguese Speaking Working Group ISFG. Vice-Presidency Spanish and Portuguese Speaking Working Group
International Society for Forensic Genetics

Niels Morling. Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health Sciences, University of
Copenhagen

David Comas. Institut de Biologia Evolutiva (CSIC-UPF), Departament de Ciències de la Salut i de la

Vida, Universitat Pompeu Fabra, Barcelona, Spain

Damian Labuda. Research Center, CHU Sainte-Justine, Université de Montréal, Montréal, Québec, Canada.

Eduardo Raimondi. PRICAI-Fundación Favaloro, Buenos Aires, Argentina.

Houssein Khodjet-el-Khil. Laboratory of Molecular Genetics, Immunology and Human Pathologies, Faculty of Sciences,
University of Tunis El Manar, Tunis, Tunisia
FUTURE RESEARCH
The n-dimensional space of protein evolution
The evolution of a protein sequence involves a dynamic process of amino acid replacements. We will explore the multiplicity of
dimensions in protein evolution both at the sequence and structure level. Specifically, the dynamics involved in the networking of
replacements around strictly conserved sites, co-evolution at protein-protein interfaces and the role of epistatic interaction
(antagonist and synergistic) associated with phenotype-genotype relationships. We will integrate population genetics, evolutionary
biology and medical genetics to widen the comprehension of the n-dimensions implicated in protein evolution.
Development of mtDNA analytical tools
We intend to improve fast algorithms for sequence clustering and automated haplogroup assignment and to release a publicly
available interface for these tasks.
Genomics of male infertility
A systematic search for rare structural variants underlying severe spermatogenic impairment will be undertaken.
Mathematical formalization of genealogies
We intend to develop the mathematical formalization of genealogies in the framework of both homogametic and heterogametic
diploid transmission (autosomal and X-chromosomal information)
Epidemiology and population genetics of degenerative ataxias
We will continue the epidemiological and population genetics studies of degenerative ataxias, with special emphasis on MachadoJoseph Disease (spinocerebellar ataxia type 3, SCA3).
Evaluating genotype diversity and persistence of Aspergillus fumigatus in the environment
1) Identification of different genotypes of A. fumigatus present on several geographical areas and distinct type of sample
(air, water, soil). Several environmental and clinical samples were collected The complete sequence of mtDNA of A.
fumigatus was started during 2011, 15% of the genome being sequenced. It is expected to finish the mtDNA sequence in
2012.
2) Analysis of the persistence of A. fumigatus wild type conidia will be evaluated through the study of autophagy, apoptosis
and death mechanisms. A suitable protocol for cell wall digestion was achieved. Promising results for cell aging are being
obtained in terms of apoptosis (TUNEL labeling) and necrosis (IP labeling), ROS and meta-caspases activities. Is is expected
to prepare a publication by the end of 2012
Migrations of human populations
The study of historical and pre-historical human migrations will be continued using a variety of genetic tools and markers, including a
specific research on a Y-chromosome lineage in the context of the ‘Back-to-Africa’ hypothesis.
Characterization of NAD salvage enzymes in humans
31
NAD salvage enzymes are implicated in a wide variety of diseases, and are targets for the development of anticancer drugs. We are
studying the mutational profile of the corresponding genes in distinct populations and also the expression pattern of these enzymes
in different human tissues. We have identified previously uncharacterized transcripts, and also discovered that these transcripts are
overexpressed in tumor cell lines. The regulation of their expression will be subject of further investigation.
Characterization of NAD salvage pathways in emerging model organisms
NAD (Nicotinamide Adenine Dinucleotide) is a coenzyme in redox reactions and also a key regulator of gene expression, DNA repair
and longevity. Thus, NAD salvage pathways are required for proper cell function. We have uncovered the evolutionary relationship
between NAD salvage enzymes in invertebrates and are now addressing the potential roles of additional isoforms in emerging model
organisms, such as the microcrustacean Daphnia magna and the amphioxus Branchiostoma lanceolatum.
Specificity of microsatellites within Aspergillus section Fumigati
Microsatellite-based PCR multiplex designed previously for Aspergillus fumigatus will be tested in a set of species belonging to
section Fumigati
Development of SNaPshot multiplexes for Aspergillus fumigatus, Pseudomonas aeruginosa and Burkholderia cenocepacia
New methods will be developed for Aspergillus fumigatus, Pseudomonas aeruginosa and Burkholderia cenocepacia genotyping
based in single nucleotide polymorphisms
Epidemiology and population genetics of degenerative ataxias.
Sequeiros J, Martins S, Silveira I. Handb Clin Neurol. 2012;103:227-51.
Population genetics and evolution of chromosomal rearrangements
Micro- and macroevolutionary consequences of genomic rearrangements will be studied; special attention will be devoted to human
inv 17q21.3.
Population and evolutionary genetics of mitochondria and NUMTS
Human mtDNAs and nuclear sequences of mitochondrial origin (NUMTs) will be analyzed in the perspective of population genetics of
extant population and evolution.
Estimating relatedness with no prior specification of any genealogy
We will develop methods for estimating relatedness between pairs of individuals of unknown linking genealogy using information
exclusively from their genetic profiles and the background inbreeding level of the population.
Testing the effects of undisclosed relatedness in kinship testing
The effect of alternative, undisclosed kinship between alleged (false) father and child in parentage testing will be studied.
Genetics of Mucolipidosis
Special attention will be devoted to Mucolipidosis type II a/ß and mutations at GNPTAB, with a particular focus on the detection of
deletions and rearrangements.
Maple Syrup Urine Disease Genetics
We will analyze the polymorphic variation associated to PP2Cm gene (BCKD phosphatase) in realation to the phenotypic disparities
associated to the variant forms of Maple Syrup Urine Disease.
A study of the impact of intronic mutations potentially causing Maple Syrup Urine Disease on splicing and evaluation of the influence
of exonic alterations, previously classified as missense, on that mechanism will be performed.
X chromosome inactivation in mammals
The characterization of genes escaping X-inactivation in Mus musculus will be specially addressed.
The paradoxical conservation of the Delta globin gene
We intend, using an evo-devo approach, to clarify why the HBD gene, although expressed at residual levels shows an unexpected low
level of diversity, and evolutionary conservation, both in humans and primates
The genetics of cultural minorities and isolates
The microevolutionary studies on NE Portugal communities of Jewish origin and of the Mirandes speakers will continue, using new
genetic markers.
Non-coding DNA in phylogeny, evolution and disease
We will identify structural conserved regions using available software for structures prediction and using new algorithms to identify
non-B DNA conformations and to analyse DNA-binding proteins interactions. The association between mitochondrial DNA deletions
with non-B DNA conformations will be specially addressed.
Computational simulation mimicking the strand-slippage replication mechanism postulated at non-coding Y chromosome short
tandem repeats (STRs) will be performed.
Phylogeography and dispersion pathways of pinewood nematode, Bursaphelenchus xylophilus
The pinewood nematode, is responsible for the current widespread pine wilt disease. Using both nuclear and mitochondrial DNA
markers, we will study it in Portugal Mainland and Madeira Island in comparison with East Asian and America isolates.
Species identification in ecology wildlife and forensics using insertion/deletion variants
We will develop a multi-functional computational workbench to assist researchers using variable-length DNA sequences in speciesidentification procedures. The workbench will provide a step-by-step environment for the alignment of target sequences, for the
selection of informative hypervariable regions, for the design of PCR primers and for the statistical and phylogenetic validation of the
species-identification process. These data might be useful for improving the high-throughput analysis of samples in wildlife forensic
investigations.

António Amorim. Director and supervisor. PhD Program in Biology, FCUP.
32

Maria João Prata. Supervisor; PhD Program in Biology, FCUP

António Amorim. GABBA, UP, Coordinator and Lecturer

António Amorim. Pós-Graduação em Ecologia e Evolução, Univ.Estadual Rio Janeiro

Leonor Gusmão. Ciencias Forenses e Patoloxía. Facultade de Medicina e Odontoloxía. Universidade de Santiago de
Compostela

António Amorim. Forensic Genetics FCUP, Director and Lecturer

Luisa Azevedo (supervision)

Mónica Marques: “Human Carbamoyl Phosphate Synthetase I. From amino acid sequence to theoretical 3D models”.
Technologic and Comparative Molecular Genetics at the University of Trás-os-Montes e Alto Douro.

Maria João Prata. Master's degree in Cell and Molecular Biology, FCUP. Lecturer

Leonor Gusmão. Mestrado em Medicina Legal e Ciências Forenses da Faculdade de Medicina de Lisboa. Lecturer

Leonor Gusmão. Forensic Genetics FCUP, Lecturer and supervisor

Ricardo Araújo. Master in Forensic Genetics (FCUP): supervisor "Multiplex SNaPshot for Aspergillus fumigatus typing on
cystic fibrosis patients" Rita Caramalho

Ricardo Araújo. Master in Dental Medicine (FMDUP): supervisor "Characterization of the oral fungal microbiota in
smokers and non-smokers" Filipa Monteiro da Silva

Sandra Martins. Forensic Genetics FCUP; supervisor

João Carlos Ramos de Azevedo Pimenta. Mecanismos mutacionais responsáveis pela dinâmica evolutiva da repetição CAG
no gene receptor de androgénio

Alexandra Lopes. Forensic Genetics FCUP. Supervisor

Ana Cristina Lima. Characterization of the 17q21.31 Inversion Polymorphism in the Portuguese Population

Leonor GusmãoForensic Genetics UP; supervision

Cláudia Gomes. Aplicações forenses do estudo de 12 X-STRs: Utilidade em diferentes casos de investigação de parentesco
biológico

Leonor Gusmão. Forensic Genetics FCUP; supervision

Marta Daniela Marques de Magalhães. POLIMORFISMOS DE INSERÇÃO/DELECÇÃO EM INVESTIGAÇÕES DE PATERNIDADE
ENVOLVENDO PARENTES PRÓXIMOS DO VERDADEIRO PAI

Luis Alvarez. Forensic Genetics FCUP; supervisor

João Carlos Aguiar Macedo Teixeira. Phylogeographic analysis of maternal lineages in the Portuguese Jewish community
PRIZES

Mónica Marques, Estefânia Martins, Gilberto Igrejas, António Amorim, Luísa AzevedoA structural insight on the impact of
disease associated mutations in NAG and ADP ligand sites in human CPSase using the Escherichia coli homologuePoster
awarded second place prize at the at the III Jornadas Nacionais de Genética e Biotecnologia (UTAD)

Isabel CastroCharacterization of human NLZ1/ZNF703 and identification of two conserved domains essential for its proper
subcellular localization

Best Poster Prize, 1º PhD Students Meeting, FMUP, December 2011.
INVITED TALKS

Leonor Gusmão. A male perspective of E and W Sub-saharan Africa. International Seminar: “Y DNA? Perspectives from
individual to group identification”

University of the Western Cape. Cape Town, South Africa. 10/03/2011.

António Amorim. A Química vista por... um geneticista. Ciclo de Conferências "A Química vista por...“, Em celebração do
Ano Internacional da Química, FCUP. Porto, Portugal. 20/05/2011.

António Amorim. GENÉTICA, REPRODUÇÕES e EVOLUÇÕES. A Origem da Evolução, Colégio Luso-Francês. Porto, Portugal.
07/01/2011.

António Amorim. A prova genética em investigação de identidade e parentesco. Semana da Ciência e Tecnologia, ES
Aurélia de Sousa. Porto, Portugal. 23/11/2011.

António Amorim. Reconstituindo o passado: da genética forense à arqueogenética. Ciclo de Palestras em Biomedicina,
Univ. Açores. Ponta Delgada, Portugal. 01/02/2011.

António Amorim. Genética Forense. V Jornadas de Análises Clínicas e de Saúde Pública , Escola Superior de Saúde,
Instituto Politécnico de Bragança. Bragança, Portugal. 21/05/2011.

António Amorim. Genética populacional - aplicações nas perspectivas forenses e de biodiversidade. Palestras PPGEE –
UERJ. Rio de Janeiro, Brazil. 27/06/2011.

António Amorim. Biologia Humana e Saúde: O ponto de VISTA de um GENETICISTA. Ordem dos Biólogos - IV Congresso
Nacional “A Biologia no Século 21”. Ponta Delgada, Portugal. 14/10/2011.
33

António Amorim. Produção e interpretação da prova genética. Workshop Prova genética em investigação de identidade e
parentesco: as dimensões pericial, judicial e societal. Porto, Portugal. 25/11/2011.

Ana Goios. The (hi)story of mouse genetics. 14th Portugaliæ Genetica. IPATIMUP, Porto, Portugal. 18/03/2011.

N. PINTO, L. GUSMÃO, W. Parson. Interpretation of mtDNA and Sex chromosome Results in the Forensic Field. Worksop
07-08/09/2011. Universidad de Alcalá, Alcalá de Henares (Madrid), Spain. 07/09/2011.

Raquel M. Silva. Tales from a NAD world. Invited seminar. CIIMAR, Porto, Portugal. 20/06/2011.

Ricardo Araújo. Genetic diversity and antifungal susceptibility of Aspergillus fumigatus from chronically colonised
Portuguese patients. 2nd Meeting of the ECMM/ISHAM Working Group on Fungal respiratory infections in Cystic Fibrosis
(Fri-CF). Angers, France. 21/06/2011.

Ricardo Araújo. Clinical impact of environmental moulds. Fernando Pessoa University. Jornadas de Microbiologia e suas
aplicações clínicas. Porto, Portugal. 04/02/2011.
ORAL PRESENTATIONS

Leonor Gusmão. Estructuración poblacional y su implicación en la elaboración de bases de datos de frecuencias alelicas
con fines forenses. II Congreso Latinoamericano de Genética Humana (II CLAGH); I Congreso Costarricense de Genética; VI
Congreso Nacional de Biología. San José, Costa Rica. 13/05/2011.

PEREIRA R, Phillips C, Pinto, N, Santos C, Santos S, Amorim A, Carracedo A, Gusmão L. A PANEL OF 46 ANCESTRYINFORMATIVE INSERTION-DELETION POLYMORPHISMS (AIM-INDELS) IN A SINGLE REACTION. 24th World Congress of the
International Society for Forensic Genetics (ISFG). Wien, Austria. 01/09/2011.

Magalhães M, Gomes C, Pereira R, Amorim A, PINTO N, Alves C, Gusmão L. WHEN THE ALLEGED FATHER IS A CLOSE
RELATIVE OF THE REAL FATHER: THE UTILITY OF INSERTION/DELETION POLYMORPHISMS. 24th World Congress of the
International Society for Forensic Genetics (ISFG). Wien, Austria. 02/09/2011.

Alexandra Lopes. Characterization of a new domain of escape on mouse XqD. “Genetics, Epigenetics and Evolution of Sex
Chromosomes”. University Paris-Diderot, Paris, France. 09/06/2011.

Alexandra Lopes. Genome-wide effects on severe spermatogenic impairment. . WTSI-Nature Genetics Symposium “The
genomics of common diseases”. Wellcome Trust Sanger Institute, Hinxton, UK. 31/08/2011.

Alexandra Lopes. Genomic structural variants in severe spermatogenic impairment. . “15ª Reunião da SPGH”. Lisboa,
Portugal. 12/11/2011.

Luísa Azevedo. Challenges in the understanding of the phenotype-genotype relashionships in ornithine transcarbamylase
deficiency. VIII international symposium, Sociedade Portuguesa de Doenças Metabólicas (SPDM). Porto. 05/11/2011.

N. Pinto. When the alleged father is a close relative of the real father: the utility of insertion/deletion polymorphisms.
24th World Congress of the International Society for Forensic Genetics (ISFG). Vienna, Austria. 02/09/2011.
34
CANCER BIOLOGY
OBJECTIVES
The main objective of the group is to progress in the understanding of the etiopathogenesis of some types of endocrine and
neuroendocrine tumours with a preferential focus in well differentiated thyroid cancer: papillary carcinoma (classic and follicular
variant) and follicular carcinoma.
Within this frame, a particular attention is paid to:
a)
genetic alterations in tyrosine kinase receptors and signal transducing molecules involved in the mitogen-activated
protein kinases (MAPK) pathway;
b)
mitochondrial alterations secondary to mitochondrial DNA mutations/deletions or to mutations in nuclear genes encoding
mitochondrial enzymes. In addition to these basic/translational approach the group has a more basic, scientific interest in
some aspects of cell cycle, tumour-microenvironment interactions and motility/invasiveness processes in cancer
Main research topics:
1.
Oncobiology of familial and sporadic thyroid tumours with an emphasis on the two major variants of papillary carcinoma
(classic and follicular type) and on the clinico pathologic and molecular features separating them from follicular
carcinoma.
2.
Role of mitochondrial alterations in the etiopathogenesis of sporadic, irradiation-induced and familial thyroid tumours
and on the oncobiology of neuroendocrine tumours (medullary thyroid carcinoma, pheochromocytoma, paraganglioma,
…)
MAIN ACHIEVEMENTS
Translational Studies
In the translational field, we have pursued the collaborative project (IPATIMUP-IPO-HSJ) initiated in the end of 2008 and aiming to
perform a thorough clinico-pathological re-evaluation of all the cases of well differentiated thyroid carcinoma diagnosed and treated
in three institutions that showed an aggressive behavior (see Future Activities). Our results highlight the importance of infiltrative
growth pattern and invasiveness over the presence of BRAF mutation in classic and follicular variant PTC for the development of
nodal metastases. We also verified the role of intratumoural lymph vessels in PTC nodal metastization and the importance of
distinguishing E-FVPTC from I-FVPTC regarding invasiveness, metastatic pattern and molecular profile. In this frame we have
published two papers (Eloy C et al, VA, 2011).
We do not discard the opportunity to gain access and characterize the unique cases that we receive as consultation/collaboration.
We had the opportunity to publish in 2011, in collaboration with Cameselle-Teijero, a case of a Tumor-in-Tumor of the thyroid with
basaloid differentiation. This unique case raises the question whether the basaloid features may represent an unusual
“differentiation switch” from preexisting SCN or indicate that the basaloid lesion may be the result of the neoplastic development
(caused by the N-RAS mutation?) of branchial pouch stem cells before they evolve to full blown SCN cells. (Eloy C et al, IJSP, 2011).
We finished the study of genetic mutations in BRAF and NRAS in an enlarged series of PTC and their nodal metastases (113 cases
comprising a total of 214 samples) and we verified that the frequency of mutations in the BRAF gene in PTC (47%), was not related to
the dimensions of the primary tumor nor the existence of extrathyroidal extension, though a statistically significant relationship was
found between the presence of BRAF mutation and histologic pattern.
Dissecting molecular pathways - Role of STAT3/IL6 pathway in thyroid cancer
Following our preliminary studies exploring signaling pathways activated by oncogenic BRAF, we tested the therapeutical effects of
inhibiting alternative pathways in thyroid cancer. We focused on the use of inhibitors of the ERK/MAPK pathway and the JAK/STAT
pathway in thyroid cancer models harboring oncogenic alterations in RET, namely PTC-derived and MTC- derived thyroid cancer cell
lines. As expected, inhibition of ERK/MAPK using a MEK1/2 inhibitor did not significantly affect the growth of activated RET cell lines,
particularly of the more aggressive MTC cells harboring RET point mutations. However, JAK inhibition significantly reduced the
proliferation, growth and motility of all thyroid cancer cell lines harboring RET alterations. We also showed that AZD1480 blocked the
cell cycle in G1 phase leading cells into a senescent state. The effects were even more dramatic in xenograft tumor growth, whereby
AZD1480 treatment caused pronounced tumor reduction, likely through inhibition of angiogenesis and induction of tumor necrosis.
We demonstrated that AZD1480 effects in our cell lines were STAT3- independent, fitting with our previous results. We also showed
that AZD1480 inhibited RET activation, probably due to off-target effects and that such inhibition led to transitory shutdown of the
ERK/MAPK pathway but to persistent inhibition of PI3K/AKT signaling. AZD1480- treated tumors showed profound downregulation of
the mTOR effector pS6, confirming our in vitro results, and pointing once again to the importance of the PI3K pathway in thyroid
cancer. In conclusion, we suggest the use of JAK inhibitor AZD1480 for the treatment of RET-harboring thyroid tumors, particularly
the ones that are refractory to conventional therapy, such as MTC (Joana Silva, PhD thesis).
Dissecting molecular pathways - Role of LRP1B in thyroid cancer
Working under the hypothesis that LRP1B modulates the extracellular medium through its endocytic activity, we have used a thyroidderived cell line stable transfected with LRP1B (8505C-empty vector and -LRP1B overexpressing cells) to collect serum-free media in
35
fibronectin-coated wells. With these media we have performed gelatin zymographies to check alterations in matrix
metalloproteinases (MMPs) activities and human antibodies arrays (growth factors and cytokines). We found a reduction of MMP2
level in LRP1B-cells. We confirmed that this difference was not attributable to different levels of MMP2 mRNA in 8505C-empty and
8505C-mLRP1B cells, as settled by qRT–PCR. We found overall changes in the amounts of several molecules quantified by using the
membrane-based antibody arrays, but the most prominently altered molecules were observed in the cytokine array. To further
characterization of other possible targets of LRP1B extracellular medium modulation identified in the arrays approach, we selected
the molecule that is most differently expressed between –empty and –LRP1B cells and proceed to its quantification by other
methods. Using ELISA strategy we confirmed the results obtained in cytokine arrays concerning this specific molecule (Hugo Prazeres
PhD thesis, MS in preparation).
Dissecting molecular pathways –Role of mTOR pathway in thyroid cancer
To evaluat the role of mTOR in thyroid cancer we characterized the expression and activation of the PI3K/AKT/mTOR pathway in a
series of human thyroid tumor specimens and explored the potential relationships between this pathway and the ERK/MAPK
pathway. We found that PI3K pathway was particularly activated in BRAFV600E-positive cases as well as in in vitro models and
suggested that BRAFV600E- mediated phosphorylation and inactivation of the tumor suppressor LKB1 could explain increased PI3K
activation. Furthermore, we demonstrated that ERK/MAPK overactivation was a strong indicator of sensitivity to mTOR pathway
inhibition by rapamycin (Faustini A, under revision).
Taking into consideration the possible shared etiopathogenic mechanisms (very frequent activation of BRAF) in thyroid cancer and
melanoma we analyzed the role of the mTOR pathway in the pathogenesis of cutaneous melanoma. Using immunohistochemistry,
we examined the expression of mTOR pathway effectors in 84 cutaneous melanoma cases and evaluated their possible association
with clinico-pathological and prognostic parameters. We also performed mutational analysis of the BRAF and NRAS genes and looked
at their relationship to the immunohistochemical data. Our results show that the mTOR pathway is activated in cutaneous melanoma
and linked to MAPK pathway activation, particularly in nodular and superficial spreading melanomas. Higher expression levels of
some mTOR pathway effectors were associated with worse prognostic parameters especially pS6 (Populo H et al, PCMR, 2011,
Helena Populo, PhD thesis).
Dissecting molecular pathways - Role of RET in thyroid cancer
Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ
line activating point mutations of the rearranged during transfection (RET) proto-oncogene. We went to assess the function of three
germ line RET variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three
portuguese kindreds of isolated AS-MTC. We found that RET variants Arg886Trp and Glu511Lys have an increased in vitro
transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not
significantly increased the number of foci and agar colonies relative to wild-type RET (RET-WT). The variants Glu511Lys and
Arg886Trp showed 10- and 12.5-fold ERK1/2 activation respectively, that was significantly higher than that observed for RET-WT
(fivefold). Increased levels of STAT1 and TCF4 activation were only observed for RET Arg886Trp (2.5- and 3-fold versus 1.2- and 2-fold
in RET-WT respectively). The three RET variants analyzed here were sensitive to treatment with sorafenib. Our results allow to
classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens. (Prazeres H et
al, ERC, 2011). We have also published a review addressing RET signaling as therapeutic target) (Prazeres H et al, JTR, 2011, Hugo
Prazeres, PhD thesis).
In a different set of studies, in collaboration with Arnaldo Videira from IBMC, we verify the pro-apoptotic role of Orthovanadate in
RET/PTC1 cells and provide in vitro data towards the comprehension of the potential of combining staurosporine and rotenone as an
anticancer tool in cells harboring RET/PTC rearrangements (Gonçalves P et al, JB & LS, 2011).
Dissecting molecular pathways – Fusion genes in thyroid tumours
In collaboration with the Department of Cancer Prevention of the Institute for Cancer Research of the Norwegian Radium Hospital of
Oslo University Hospital we are developing a work using an oligo microarray-based approach for simultaneous analysis of all known
and predicted fusion gene variants in isolated RNA. We have analysed a series of FTA, FTC, PTC, FVPTC and oncocytic variant of PTC
and the TPC1 thyroid cancer cell line. The candidate fusion genes suggested by the results in the oligo-microarray and never detected
in thyroid tumours, were tested by RT-PCR approach. Within the thyroid tumours tested, only well known, previously reported fusion
genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3 and PAX8-PPARG
fusion genes in thyroid tumourigenesis (Celestino R, PhD thesis). The molecular alterations underlying follicular Hürthle cell
carcinomas (FHCC) are largely unknown. In an attempt to clarify this issue, we analyzed a series of Hürthle cell tumours for the
presence of RET/PTC and PAX8/PPARG rearrangements and BRAF, HRAS and NRAS mutations. Our study disclosed a significant
association between RET/PTC rearrangement and FHCC with a solid growth pattern, raising the possibility of using tyrosine kinase
inhibitors for treating patients with FHCC which are often refractory to radioiodine treatment (de Vries & Celestino R, in press in
Histopathology, Celestino R PhD thesis).
Ethiopathogenesis of radiation induced cancer
In this item we are following-up a cohort of individuals that suffered epilation by scalp X-ray irradiation for the Tinea capitis
treatment. We have successfully followed-up 26% of the cohort (1135 individuals were observed and 248 individuals deceased).
Besides the other lesions followed in these cohort , we have verified an overall prevalence of BCC of 8.0% and of multiple BCC of
2.4%. Both total (14.7%) and multiple BCC (6.6%) were significantly more common in the individuals who had received a higher
radiation dose. Multiple BCC was more prevalent (3.7%) in younger irradiated individuals and total BCC (9.4%) in women. Participants
with BCC and without BCC presented similar skin pigmentation. We concluded that younger age at irradiation, higher dose and
female gender increased the risk of developing BCC in these irradiated individuals. (Boaventura P, Pos-Doc Project) (Boaventura P,
EJD, 2011)
The results on thyroid pathology, were published in 2011 in the “Lancet Infectious Diseases”, as a letter entitled: “Head and neck
lesions in a cohort irradiated in childhood for tinea capitis treatment”( Boaventura P, LID, 2011).
Mitochondria and cancer-Tumourigenic and metabolic effects of mitochondrial dysfunction
In this project we aimed to prove that OXPHOS dysfunction, caused by mutations in mtDNA or nuclear-encoded OXPHOS genes,
underlies the Warburg effect in tumour cells and is essential for the survival of tumour cells, leading to the acquisition of phenotypic
properties involved in tumour progression.
36
We have built a model of OXPHOS dysfunction, where we have 143B parental cells, the 143B¿0 (derived from 143B after mtDNA
depletion), cybrids with WT mtDNA (normal OXPHOS, control cells), cybrids with a mutation in the tRNAleu (tRNA cybrid, defective
OXPHOS) and cybrids containing a mutation in ND gene1 (ND1 cybrid, defective OXPHOS).
We first showed that O2 consumption (indicator of OXPHOS function) was significantly reduced in tRNA cybrids compared with WT
cybrids (collaborative work with Carlos Palmeira, CNCB, Coimbra); the OXPHOS dysfunction was associated with an increased
glycolytic rate as seen by the glucose/lactate flux (collaborative work with Ana Teixeira, IBET, Oeiras).
To assess the tumourigenic potential of mutant vs. WT cybrids we inoculated WT and tRNA cybrids in nude mice and observed that,
while both cybrids were able to produce tumours, tRNA cybrids displayed increased tumour growth and enhanced metastatic
potential: 3/14 (22%) mice injected with tRNA cybrids presented lung metastasis, whereas no mice injected with WT cybrids
developed lung metastasis. Cell growth in vitro did not show differences between the two cybrids, while apoptosis upon
staurosporine stimulation was decreased in tRNA cybrids. Using time-lapse microscopy we could also demonstrate that tRNA cybrids
display a significant motility and migration capacity, as seen by wound healing assays and single-cell motility, and this effect was
associated with increased levels of activated RhoA. These two parameters – decreased apoptosis and increased motility/migration –
may, at least in part, explain the observations in vivo and confirm the pro-tumourigenic effects of OXPHOS dysfunction
Mitochondria and cancer - Screening of mutations in SDH genes in hereditary and apparently sporadic paragangliomas (PGL)
In collaboration with IPO (Portuguese Institute of Oncology), Porto we are studying Portuguese patients from northern Portugal for
the presence of germline SDH mutations. At the moment, we have analysed 30 patients who developed abdominal PGL, of which 28
were apparently sporadic cases and one was hereditary (two patients from one family). Seventeen apparently sporadic cases (61%)
carried pathogenic germline mutations, as did the hereditary PGL. With the exception of one case that presented a SDHC missense
mutation, the remaining 16 apparently sporadic PGL presented SDHB mutations; of these, three showed missense mutations, three
showed frameshift mutations, whereas ten cases presented a large deletion encompassing exon 1 plus the promotor of SDHB. The
deletion breakpoint was the same in all cases. The hereditary PGL presented a frameshift mutation in SDHD. Our findings revealed
that a very high proportion (61%) of Portuguese apparently sporadic PGLs arises as a consequence of germline mutations and that
most of the patients presented a large SDHB deletion encompassing exon 1 and promotor; the finding that the deleted allele shows
the same haplotype in all patients suggests a founder effect for this particular deletion, which would be the first founder mutation in
SDHB in the Portuguese population.
STAT3 regulation and role in thyroid cancer.
New therapies in thyroid cancer: the use of MEK inhbitiors and JAK inhibitors and combination therapies. Work developed in MSKCC,
New York, NY, in collaboration with Dr Jacqueline F. Bromberg, on behalf of Joana Silva's PhD project.
Fusion gene microarray-based approach and RNA-sequencing technology in thyroid tumours
Collaboration with the Department of Cancer Prevention of the Institute for Cancer Research of the Norwegian Radium Hospital of
Oslo University Hospital for the use of a fusion gene microarray-based approach that allow the simultaneous analysis of all known
and predicted fusion gene variants in thyroid tumours, and the use of RNA-sequencing technology in follicular carcinomas.Work
developed on behalf of Ricardo Celestino PhD project.Collaboration with the Department of Cancer Prevention of the Institute for
Cancer Research of the Norwegian Radium Hospital of Oslo University Hospital for the use of a fusion gene microarray-based
approach that allow the simultaneous analysis of all known and predicted fusion gene variants in thyroid tumours, and the use of
RNA-sequencing technology in follicular carcinomas.
ENETs Tumour registry
As a member of GE-TNE of SPEDM we are evaluating the future enrolment of a Portuguese NETs registry in the ENETs tumour
registry. Work developed on behalf of João Vinagre PhD project.
Role of mitochondrial function in the regulation of the programmed cell death.
Valdemar Máximo and Paula Soares (IPATIMUP) & Institute of Molecular and Cellular Biology/Institute of Biomedical Engineering
(IBMC/INEB), Porto, Portugal – Principal Investigator involved: Arnaldo Videira
Description - We started, in 2008, a acollaboration with Professor Arnaldo Videira from IBMC. The establishment of this collaboration
has the primary aim the study of the role of mitochondrial function in the regulation of the programmed cell death both in
Neurospora crassa model as well as in human cancer cell lines models.
This collaboration was reinforced in 2008 with the recruitment of a PhD student (António Pedro da Rocha Cardoso Gonçalves)
supervised by Professor Arnaldo Videira, and intends to study the role of mitochondrial function in the regulation of the
programmed cell death both in Neurospora crassa model as well as in mammalian cell lines model, namely in human thyroid
carcinoma-derived cell lines. The PhD research grant is funded by Fundação Calouste Gulbenkian.
Role of mitochondrial function and metabolism in human tumourigenesis.
Valdemar Máximo & Jorge Lima (IPATIMUP) & Centre for Neuroscience and Cell Biology (CNC), Coimbra, Portugal – Principal
Investigator involved: Carlos Palmeira & Institute of Experimental and Technologic Biology (IBET), Oeiras, Portugal – Principal
Investigator involved: Ana Teixeira
Description - In order to understand as fully as possible the role of mitochondrial function and metabolism in human tumourigenesis
we developed contacts with two of the most reputed Portuguese group [one from Coimbra (CNC) other Lisbon IBET)] specialists in
metabolic diseases and cellular metabolic pathways analysis. These contacts led to the establishment of a network between
IPATIMUP (experts in oncobiology), CNC (experts in metabolic disorders) and IBET (experts on cell metabolism pathways) and to the
design of a joint project entitled “Targeting the Warburg effect for cancer therapy” that was funded by IPATIMUP (See Approved
Projects).
Role of the mitochondrial biogenesis machinery in mitochondrion-rich tumours .
Valdemar Máximo (IPATIMUP) & Department of Cell Physiology and Metabolism of the University of Geneva, Geneva, Switzerland –
Principal Investigator involved: Luca Scorrano
37
Connected with the PhD projecto of the BSc André Emanuel Ferreira da Silva (entitled “Role of the mitochondrial biogenesis
machinery in mitochondrion-rich tumours”) a collaboration with Professor Luca Scorrano was established.
Professor Luca Scorrano is an expert in the regulation of mitochondrial biogenesis, namely in the mitochondrial fission processes as
well as in the role of mitochondria in programmed cell death and autophagy.
Role of mitochondrial function and metabolism in human tumourigenesis.
Valdemar Máximo & Jorge Lima (IPATIMUP) & Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, USA – Principal
Investigator involved: Keshav Singh
Professor Keshav Singh is Associate Professor of Oncology/Full Member at the Department of Cancer Genetics of RPCI, founding
Editor-In-Chief of the Journal Mitochondrion and founder of The Mitochondria Research Society, among other relevant facts. He was
also co-supervisor of the post-doctoral studies of Jorge Lima and specialized in cybrid construction and mitochondrial function. We
have established a collaboration under the project “Targeting the Warburg effect for cancer therapy”.
Role of GRIM-19 in Human tumorigenesis.
Valdemar Máximo & Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, USA –
Principal Investigator involved: Dhan Kalvakolanu.
Professor Dhan Kalvakolanu is an expert in the regulation of gene transcription and signal transduction by cytokines; tumour cell
growth control; and regulation of cell death-activating genes. Professor Dhan Kalvakolanu has identified GRIM-19 and its role in cell
death regulation. Professor Kalvakolanu on a visit to Europe he visited us and suggested a collaboration under the project: “Role of
GRIM-19 in cancer development”.
GRIM-19, a novel protein involved in cell apoptosis: structure-function characterization .&
European Synchrotron Radiation Facility (ESRF), Grenoble, France – Principal Investigator involved: Daniele de Sanctis.
Valdemar Máximo & Instituto de Tecnologia Química e Biológica (ITQB), Oeiras, Portugal – Principal Investigator involved: Isabel
Bento & European Synchrotron Radiation Facility (ESRF), Grenoble, France – Principal Investigator involved: Daniele de Sanctis.
In the beginning of 2010 we started a collaboration with Doctor Isabel Bento from ITQB and Doctor Daniele de Sanctis from ESRF in
order to progress in the understanding of the role of GRIM-19 in cell biology. These contacts led to the establishment of a network
between ITQB, IPATIMUP and ESRF and to the design of a joint project entitled “GRIM-19, a novel protein involved in cell apoptosis:
structure-function characterization” and to a funding proposal to the FCT in December 2009. The proposal was recommended for
funding by FCT – Ref.: PTDC/BIA-PRO/113064/2009
Research Exchange of the International Federation of Medical Students´ Associations
Co-supervision of a medical student from Russia within Research Exchange of the International Federation of Medical Students´
Associations during 1 month. Jorge Lima & Department of Endocrinology, Portuguese Institute of Oncology (Porto, Portugal), Dr
Isabel Torres
A collaboration for the genetic screening of patients with sporadic and hereditary forms of paraganglioma and
pheochromocytoma
Ethiopatogenesis of thyroid cancer. Several works in the molecular characterization of thyroid tumors with emphasis in rare cases.
collaboration with José Cameselle-Teijeiro from the Universidade de Santiago de Compostela, Spain.
In depth genetic characterization of familial and sporadic thyroid tumours
Collaboration with Robert Hofstra from the University Medical Center Groningen, Groningen, Holland. Use of deep sequencing
methods in order to identify molecular alterations in familial forms of thyroid cancer
Fusion gene microarray-based approach in thyroid tumours
Collaboration with Ragnhild Lothe and Rolf Stokheim from the Institute for Cancer Research, Oslo, Norway.
FUTURE RESEARCH
Translational studies
Following the collaborative project involving pathologists, scientists and clinicians from IPATIMUP, IPO-Porto and H S Joao we aim to
progress in the disclosure of biomarkers with diagnostic, prognostic and therapeutic importance. A particular emphasis will be put in
the role of TGF-beta pathway in papillary thyroid cancer. We will also conduct studies exploring the presence of BRAF mutations and
the expression of iodine metabolizing genes and response to therapy (Miguel Melo PhD thesis). We will pursue the studies using high
throughput methods to evaluate the presence of new rearrangements in thyroid tumours in collaboration with Raghnild Lothe and
Rolf Stockeinhem (Celestino R, PhD thesis).
Dissecting molecular pathways
To go further in the study of BRAF V600E mutation in thyroid cancer and to address therapeutic options we intend to develop a
suitable animal model. Therefore, we aim to establish a thyroid targeted- BRAFV600E transgenic zebrafish model so we can study the
role of activated BRAFV600E in thyroid cancer development and progression. Taking into account our previous work we will validate
the animal model by evaluating MAPK and mTOR pathway activation in thyroid targeted- BRAFV600E transgenic zebrafish tumours.
We intend also to identify and validate new proteins and pathways with a role in thyroid tumorigenesis by doing gene expression
arrays of the BRAFV600E transgenic zebrafish tumours. These arrays will be filtered against arrays of BRAFV600E-transgenic mice
thyroid tumours (from previous work of our group) and human thyroid cancer (publicly available). Finally we will test drugs or
combination of drugs, targeting the already know pathways (MAPK and mTOR) .
Irradiation and disease - epidemiologic and biologic evaluation of a cohort irradiated in childhood for tinea capitis treatment
The association between low dose (LD) exposure and later cardiovascular disease (CVD) is still controversial. Scalp irradiation for
tinea capitis treatment performed at childhood, may be a risk for the development of carotid stenosis in adult age. The aim of the
study is to evaluate the atherosclerosis risk of the tinea capitis LDirradiated individuals inviting to the study the 1367 individuals that
we have already observed.
38
A B-mode carotid US for intima media thickness measurement will be performed. We will total cholesterol, LDL-cholesterol, HDLcholesterol, triglycerides, glucose (traditional risk factors) and apoB, homocysteine, hsCRP, IL-6 (new risk factors). We will evaluate
DNA damage using the Alkaline Comet and the g-H2AX assays on lymphocytes from participants and controls.
This study can bring further knowledge in order to reduce the burden of radiation induced atherosclerotic disease(Boaventura P PosDoc project and Pereira D).
Mitochondria and cancer - Metabolome of mitochondrial dysfunction in cancer
In this project, we will take advantage of cybrids as cell model system, already built and well characterized in our lab, to address our
question: what are the metabolic pathways that are activated, or inactivated, as a consequence of mtDNA mutations/OXPHOS
dysfunction?
The model consists of five cell lines that share the same nuclear background, only differing in the mtDNA sequence, that can either
be wild-type (OXPHOS-proficient), or harbouring a mtDNA pathogenic mutation (OXPHOS-deficient). Using this novel approach, we
will profile the whole metabolome of OXPHOS-deficient and proficient cells through a metabolomics platform that identifies and
quantifies 400-800 metabolites; the findings will be validated in the five cell lines and in derived mouse xenografts.

José Manuel Lopes. PhD programme in " Medicina e Oncologia Molecular", FMUP

Patrícia Manuel Costa e Castro. PhD module of molecular techniques in the Life and Health Science Research Institute
(ICVS), School of Health Sciences, University of Minho , 2011, with the talk about “FISH”.

Patrícia Manuel Costa e Castro. Teaching monitor of the practical module (molecular biology techniques) of the PhD
program in human pathology and molecular genetics

Valdemar Máximo. Doctoral Program in Medicine and Molecular Oncology; Doctoral Program in Genetics and Molecular
Pathology; Doctoral Program in Biomedicine; Doctoral Program in Biomedical Sciences - Professor and co-coordinator of
the Module of Oncobiology

Valdemar Máximo. Graduate Program in Areas of Basic and Applied Biology (Porto); Gulbenkian PhD Program (Oeiras);

Professor of the Module of Oncobiology

Valdemar Máximo. Doctoral Program in Biomedicine and Experiental Biology (Coimbra) - Professor of the Module of
Metabolic Remodeling in Cancer

Jorge Lima. Graduate Program in Areas of Basic and Applied Biology (Porto); Gulbenkian PhD Program (Oeiras); Professor
of the Module of Oncobiology

Paula Soares. Graduate Program in Areas of Basic and Applied Biology (Porto); Gulbenkian PhD Program (Oeiras);
Professor of the Module of Oncobiology

Paula Soares. Doctoral Program in Medicine and Molecular Oncology (FMUP); Doctoral Program in Genetics and
Molecular Patholog (ICBAS/FMUP)y; Doctoral Program in Biomedicine (FMUP); Doctoral Program in Biomedical Sciences
(ICBAS)

Hugo Prazeres - PhD student with the thesis "Molecular and functional alterations in FNMTC." (Co-supervisors: Paula
Soares and Teresa Martins, U Coimbra). Concluded in January 2011, FMUP

Helena Isabel Martins Pópulo - PhD student with the thesis “Relevance of mTOR pathway in the initiation/progression of
human tumours” (Co-supervisors Paula Soares and Jose Manuel Lopes). Concluded in July 2011, FMUPPhD programme in
in Biomedicine. .

Joana Silva - PhD student with the thesis "Signal transducer and activator of transcription (STAT) 3 in tumors with
oncogenic BRAF activation". (Co-supervisors: Paula Soares and Jacqueline F. Bromberg, MSKC,NY, USA)PhD in
Biomedicine, FMUP.

Catarina Eloy - PhD student with the thesis " Papillary thyroid carcinoma: identification of prognosis biomarkers through
genotypic and phenotypic analysis." (Supervisor:M Sobrinho-Simões) FMUP

Ricardo Celestino - PhD student with the thesis "Structural and functional effects of chromosomal rearrangements in solid
tumours: Neoplastic thyroid lesions as model." (Co-supervisors P Soares and Giovanni Tallini, U Pisa) PhD programme in
pathology and molecular genetics - ICBAS/FMUP

João Vinagre PhD student with the thesis "Unraveling the genetics of neuroendocrine tumors by high throughput
methods".(Co-supervisors Paula Soares and José Manuel Lopes)PhD programme in pathology and molecular genetics ICBAS/FMUP

Jorge LimaAna Lourenço de Almeida - PhD student with the thesis "An approach to thyroid cancer targeted-therapy using
transgenic zebrafish as a model". Supervisors Paula Soares (IPATIMUP) and Miguel Godinho Ferreira (IGC-Oeiras)

Doctoral Program in Medicine and Molecular Oncology (FMUP); Doctoral Program in Genetics and Molecular Patholog
(ICBAS/FMUP)y; Doctoral Program in Biomedicine (FMUP); Doctoral Program in Biomedical Sciences (ICBAS)Pathology and
Molecular Genetics PhD Programme - ICBAS/FMUP

André Emanuel Ferreira da Silva - PhD student with the thesis "Role of the mitochondrial biogenesis machinery in the
mitochondrion-rich tumours. " (Co-supervisors Valdemar Máximo and Luca Scorrano)PhD Program in Biomedicine - FMUP

Miguel Melo - PhD student with the thesis "Biomarcadores moleculares de prognóstico e selecção terapêutica em
carcinomas da tiróide de diferenciação folicular" (Co-supervisors Manuel Cavalheiro and Paula Soares)PhD programme im
Molecular Oncology and Medical Faculty of the University of Coimbra
39

Patrícia Manuel Costa e CastroMaster and PhD module of molecular techniques in the Life and Health Science Research
Institute (ICVS), School of Health Sciences, University of Minho , 2011, with the talk about “FISH”.

Paula SoaresMaster of Science in medicine and Molecular Oncology, FMUP. Professor of the Module of Oncobiology and
Endocrinology

Valdemar MáximoMaster of Science in medicine and Molecular Oncology, FMUP. Professor and co-coordinator of the
Module of Oncobiology

Sandra Raquel de Oliveira Tavares " Identificação de biomarcadores terapêuticos de melanoma." July 2011. Supervisor
Paula SoaresMaster Program in Molecular Biomedicine, University of Aveiro

Marcelo José Marques Correia "“Role of GRIM-19 and interacting proteins in human tumours” Supervisor Valdemar
Máximo.Master degree in Molecular and Cellular Biology, Faculdade de Ciências e Tecnologia da Universidade de
Coimbra. Completed in September 2011

Ana Isabel Mendes Dias “Role of GRIM-19 and STAT3 interaction in renal cell tumors: clear cell renal cell carcinoma as a
model.”. Supervisor Valdemar Máximo. Master in Human Biology and Environment, Faculdade de Ciências da
Universidade de Lisboa

Joana Peixoto "Study of SDH mutations in pheocromocytoma"Master Program in Molecular Biomedicine, Universidade de
Aveiro

Maria Adélia “ Genetic alterations in parathyroid tumours” (Supervisor P Soares).Master Program in Molecular Oncology,
ICBAS
PRIZES

Paula Boaventura, Dina Pereira, Paula Soares, José Teixeira GomesPrize ACS-MERCK SERONO in cancer Epidemiology
(2010) with the work “Irradiação por Tinea Capitis e Risco de Cancro”. The study was directed to the detection of possible
sequelae resulting from X-ray scalp epilation used in tinea capitis treatment. The individuals submitted to this therapeutic
intervention were mainly children and were registered at the former Dispensário Central de Higiene Social do Porto. All
these registered individuals were searched and to the ones found a free clinical observation was offered. An increased
prevalence of head and neck neoplasias was observed, namely thyroid cancer, basal cell carcinoma and meningioma.
Concerning Public Health this project had (and still has) as a priority to improve the health care of these individuals,
having in mind the implications of the radiation treatment that they experienced and the fact that most of them was not
aware of these implications.

Joana Silva, Laura Daly, Ana Almeida, James Fagin, Jeffrey Knauf, MS Sobrinho-Simoes, Jacqueline F Bromberg & Paula
SoaresSTAT3 regulation and role in thyroid cancer. Award for Best poster in the category of Oncobiology. 2011 I3S
Scientific Retreat, Póvoa do Varzim, Portugal

Joana Silva, Laura Daly, Ana Almeida, Jeffrey Knauf, James Fagin, MS Sobrinho Simoes, Jacqueline Bromberg & Paula
SoaresSTAT3 role and regulation in thyroid cancer3rd Prize for Best Oral Presentation. International Medical Postgraduate
Conference,2011, Hradec Kralove, Czech Republic

Lado-Abeal J, Celestino R, Bravo SB, Garcia-Rendueles ME, de la Calzada J, Castro I, et al. Identification of a paired box
gene 8-peroxisome proliferator-activated receptor gamma (PAX8-PPARgamma) rearrangement mosaicism in a patient
with an autonomous functioning follicular thyroid carcinoma bearing an activating mutation in the TSH receptor. Endocr
Relat Cancer. 17(3):599-610, 2010. Fundación de la Sociedad Española de Endocrinología y Nutrición (FSEEN). Winning
work

Hugo Prazeres. Young Investigator Award – European Society of Human GeneticsYoung Investigator Award

João Vinagre. ETA travel grant. European Thyroid Association

João Vinagre. Prémio Amizade "Porto-Ferrol"Grant for research in medical sciences attributed by Rotary Club
International
INVITED TALKS

Valdemar Máximo. Changes of metabolic enzymes in cancer. 15th Annual Meeting of the Portuguese Society for Human
Genetics. Lisbon, Portugal. 11/11/2011.

Valdemar Máximo. Thyroid cancer: a metabolic disorder. International Advanced Course on Endocrinology, Diabetes and
Nutrition. Porto, Portugal. 11/02/2011.

Paula Soares. Patologia molecular dos tumores da tireoide. XII Congresso Técnico de Anatomia Patológica. Espinho,
Portugal. 21/05/2011.

Paula Soares. Valor prognóstico das variantes moleculares de carcinoma da tireoide. 2º CURSO DE CIRURGIA ENDÓCRINA
E CERVICAL DO H. S. JOÃO. Porto, Portugal. 21/10/201.
ORAL PRESENTATIONS

Joana Silva. STAT3 regulation and functional role in thyroid cancer. International Medical Postgraduate Conference,2011.
Hradec Kralove, Czech Republic. 11/11/2011.

Vinagre J, Falcão M, Eloy C, Soares P, Lopes JM. "A clear cell renal carcinoma causing resistance to VEGF inhibitors in an
Age-related Macular Degeneration (AMD)?". 23rd European Congress of Pathology (ECP 2011). Helsinki, Finland.
28/09/2011.
40

Vinagre J, Pópulo H, Faustino A, Tavares S, Lopes JM, Soares P. "BRAF and GNAQ mutation cellular effects in mTOR
pathway activation in human cells". 23rd European Congress of Pathology (ECP2011). Helsinki, Finland. 29/08/2012.

Vinagre J, Pópulo H, Azevedo F, Soares P, Lopes JM. "Expression of pS6 Ser235/236 effector of mTOR pathway may be a
prognostic parameter in patients with cutaneous melanomas". 23rd European Congress of Pathology (ECP2011). Helsinki,
Finland. 30/08/2012.

Joana Nunes. “The Role of Mitochondrial Dysfunction in the Acquisition of the Warburg Effect in Tumour Cells: insights
into cancer metabolism". “IJUP’11 – 4º Encontro de Jovens Investigadores da Universidade do Porto” . Porto. 18/02/2011.

Hugo Prazeres. Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular
microenvironment of thyroid cancer cells. European Human Genetics Conference. Amsterdam. 28/05/2011.

Hugo Prazeres. Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular
microenvironment of thyroid cancer cells. I3S Scientific Retreat 2011. Povoa de Varzim, Portugal. 07/05/2011.
41
CARCINOGENESIS
OBJECTIVES
The main objective of the group is to identify alterations of mucins and mucin glycosylation, associated with gastric carcinoma and
precancerous lesions, that may be relevant for the development of diagnostic and therapeutic strategies. We are also engaged in
understanding the molecular mechanisms involved in the development of gastric carcinogenesis with emphasis on the identification
of transcriptional pathways responsible for cancer/pre-cancer transdifferentiation, as well as to extend our expertise on other cancer
models (ex: mammary cancer from dogs).
MAIN ACHIEVEMENTS
Molecular mechanisms involved in gastric intestinal metaplasia (IM).
We identified, in an epidemiologic study in Mozambique, that CDX2 expression, as a surrogate endpoint to intestinal differentiatiuon
of the gastric mucosa, was associated with infection by high virulence Helicobacter strains and with low vegetable consumption both factors classically associated with an aggressive environmental setting for gastric cancer development (Peleteiro B et al, in press
Eur J Cancer Prev).
A major breakthrough of the research in 2011 was the identification of a CDX2 autoregulatory loop, active in vivo in lesions of
intestinal metaplasia, that strongly indicates that upon CDX2 triggering there are limited chances to revert the metaplasia
phenotype, partly explaining the limited success of Helicobacter pylori eradication strategies in reducing the risk for cancer
progression after IM establishment (Barros R et al, Gut 2011). Helicobacter pylori was directly identified, both using in vitro and
mouse models, as a CDX2 inducer through the BMP-SMAD pathway and curiously by also negatively interacting with the SOX2 gastric
transcription factor (Camilo V et al, manuscript submitted).
Finally, a new translational inhibitory mechanism of CDX2 mediated by MEX3A in P bodies was identified using a genome-wide
expression screening. These are completely novel results showing for the first time that a major homeotic differentiation protein
involved in GI cancer, CDX2, is subjected to post-transcriptional regulation (Pereira B et al, manuscript submitted). An additional
observation was that expression of Sialyl-Tn cancer-associated carbohydrate, described by the group in IM in the early nineties, is
associted with overexpression of the ST6GalNAc-I enzyme (Marcos NT et al, Front Biosci. ELITE ed, 2011).
Glycosylation alterations in gastric carcinogenesis.
A recent technique developed by a group in the University of Uppsala - Proximity Ligation Assay (PLA) - was adapted by our group for
glycopeptide identification and new glycoforms - T/SLe(a) -MUC2, STn/T/SLe(a) /SLe(x) -MUC5AC and STn/T/SLe(a) /SLe(x) -MUC6 were identified for the first time allowing sensitive detection of specific aberrant mucin glycoforms in cancer, increasing specificity to
the use of antibodies either to the mucin protein backbone or the O-glycan haptens alone (Pinto R et al, in press J cell Mol Med).
A PhD student of the group, Lara Silva, obtained a new monoclonal antibody, glycoform specific, for the ovarian carcinoma mucin
MUC16/CA125 and characterization is being performed and a manuscript is in advanced phase of preparation.
We have characterized the expression of ST6GalNAc-I enzyme in gastric tissues using a novel unique and specific monoclonal
antibody to this enzyme. We showed that the expression of Sialyl-Tn cancer-associated carbohydrate antigen in intestinal metaplasia
and gastric carcinoma is associated with overexpression of the ST6GalNAc-I (Marcos NT et al, Front Biosci. ELITE ed, 2011). In
addition, it was demonstrated for the first time that E-cadherin is regulated by glycosylation controlled by specific
glycosyltransferases (GnT-III and GnT-V).
We have showed that GnT-III-mediated glycosylation has a stabilizer effect on E-cadherin whereas GnT-V-mediated glycosylation as a
destabilizer effect. These novel regulatory mechanism of E-cadherin functions was further validated in human gastric cancer clinical
samples (Pinho SS et al. JBC under revision).
Furthermore, we have demonstrated for the first time that Mgat3 gene (that encodes the GnT-III glycosyltransferase) is a driver gene
during Epithelial to Mesenchymal Transition (EMT) and the reverted process Mesenchymal to Epithelial Transition (MET).
Interestingly, we found that E-cadherin is specifically regulated by GnT-III-mediated glycosylation during EMT/MET .This is the first
report addressing the role of a glycosyltransferase modulating E-cadherin function during the EMT/MET process. (Pinho et al PLoS
ONE 2012, in press).
The group has also shown that sialylation regulates galectin-3/ligand interplay during tumour progression (de Oliveira et al., Int J Dev
Biol 2011). In collaboration with INEB, with the purpose of testing its inhibitory effects on Helicobacter pylori binding, we have
collaborated in the evaluation of the effect of surface chemistry on H. pylori adhesion, viability, and morphology. (Parreira et al., J
Biomed Mater Res A. 2011 Dec 1;99(3):344-53).
Faculty of Health Sciences of the University of Copenhagen - Ulla Mandel and Henrik Clausen
Collaboration has been fundamental for characterization of carbohydrate antigens and glycosyltransferases using unique monoclonal
antibodies. We hhave been collaborating with this group for building glycopeptide arrays in the context of an European project. Two
PhD students of the group (Lara Silva and Diana Campos) are doing joint PhD thesis. We regularly collaborate in pos-graduate
teaching activities at the University of Copenhagen – PhD Glycobiology Course.
INSERM, Nantes – Jacques Le Pendu
This collaboration has been critical for the prosecution of the study of Secretor and Lewis phenotypes/genotypes, due to the unique
expertise of Jacques Le Pendu in the field. We are currently folllowing an interesting possibility of cooperation of Helicobacter pylori
in glycoengeneering the host for certain Calicivirus strain infections.
42
INSERM, Strasbourg – Jean-Noel Freund
This collaboration is essential for the study of CDX2 regulation in intestinal metaplasia using animal models. A PhD thesis (Rita
Barros) was completed between our two groups and joint projects are being developed.
Consortium for Functional Glycomics – The Scripps Research Institute, CA, USA - James Paulson
This collaboration (Celso Reis is a member of the Consortium) has provided the use of resources of the Consortium (funded by the
NIH), including Microarray analysis and knock-out mice.
Umea University, Sweden – Thomas Boren
This collaboration has contributed for establishing H.pylori adhesion assays. A PhD thesis (Ana Magalhaes) was completed in
2011between our two groups.
University of Cologne - Tilo Schwientek
This collaboration is essential for the identification of the cancer serum glycoproteome in the context of a European project and its
follow-up.
Osaka University and RIKEN, Japan – Naoyuki Taniguchi
This collaboration is essential for the study of N-glycosylation in cancer, by providing access to unique resources including
monoclonal antibodies and due to the recognized expertise of the Japanese group in the field.
University of Uppsala - Ola Soderberg
This collaboration has allowed the successful establishment of Proximity-Ligation assays for identification of glycopeptide structures
in situ.
Utrecht University Clinic of Companion Animals, The Netherlands - Gerard Rutteman
This collaboration is important for the study of dog mammary tumours. A PhD thesis (Joana Oliveira) is being performed between the
two groups.
Institut Pasteur, France - Eliette Touati
This collaboration is essential for the study of Helicobacter Pylori using animal models. A PhD thesis (Joana Gomes) is being
developed between the two groups.
INSERM, Grenoble - Marc Billaud
This collaboration is essential for the study of MEX3A, identified for the first time in humans by this group, in the P-bodies
degradation of CDX2 which is being evaluated by our group.
Biocenter Oulu, Oulu Centre for Cell-Matrix Research, Department of Medical Biochemistry and Molecular Biology, University of
Oulu, Finland. - Aki Manninen
This collaboration is very promising for the assessment of galactan efficacy in vitro and also in vivo in a metastasis assay conducted in
nude mice.
CEDOC, Lisboa, Portugal - António Guerreiro
Nutraceutic food in the protection of intestinalization of gastric mucosa in mice infected with Helicobacter pylori.
Instituto de Oncologia de Lisboa, Portugal - Paula Chaves
We are collaborating with the group in Lisbon using Barrett's oesophagus as a parallel model to intestinal metaplasia.
FUTURE RESEARCH
Future perspectives - Glycobiology research group
The Glycobiology research group will focus on the role that glycans play in carcinogenesis and gastric cancer progression. The group
aims at identifying the glycosyltransferases responsible for the glycosylation alterations induced by H. pylori and understanding their
role in H. pylori adhesion and chronic infection. Furthermore the group will also continue to addresses the role of glycans in key
processes in cancer cell biology, including glycan-mediated cell-cell communication, cancer-cell invasion and metastization. In
addition, the group will continue to develop glycoproteomic strategies for identification of biomarkers that can be used for cancer
detection. Based on the expertise of the team in the field, the group will focus on the following objectives:
The group aims to characterize the role of glycans for H. pylori adhesion/infection and to develop novel anti-adhesion therapeutic
strategies based on carbohydrates/analogs. The following approaches will be used:

We will evaluate in gastric biopsies of individuals with H. pylori infection the glycosylation alterations induced by the
bacteria and characterize the glycosyltransferases repertoire responsible for such glycophenotype modifications. This
evaluation will allow the validation of our in vitro findings previously published in the Journal of Clinical Investigation
118:2325-36 (2008). These analyses will be combined with the detailed characterization of the adhesins of the H pylori
strains infecting each individual. The analysis of adhesins will be performed by protein detection in Western Blots using
specific antibodies, and in functional assays using labelled glycans. This comprehensive study of both the H. pylori
adhesins expression, the glycosyltransferases expression and the glycophenotype will provide insights into mechanisms
contributing for the H. pylori chronic infection of the gastric mucosa.

We will continue the development of novel strategies for inhibition of H. pylori adhesion and infection. This approach is
being developed within an on-going collaboration with Dr. Cristina Martins from INEB. In this project we are developing
and testing chitosan microspheres modified with synthetic carbohydrates receptors for inhibition of H. pylori adhesion,
using cell line models expressing specific glycan receptors, gastric mucosa of genetically modified mice (previously
published by our group), and human gastric mucosas.
The group will continue to evaluate the role of glycans in disease and particularly on the cancer cell behaviour addressing the
molecular mechanisms controlling glycosylation of key proteins. Various lines of research are going to be developed:
1.1) We will continue to analyse the role of E-cadherin glycosylation in cancer cell behaviour. We will genetically manipulate
gastric cancer cell lines by transfecting specific glycosyltransferases and evaluate the E-cadherin glycosylation
modifications and its impact in cancer cell biology. We will characterize the different N-glycans structures attached to E-
43
cadherin; we will evaluate the biological role of each E-cadherin N-glycan structure in cancer by transfecting cancer cell
lines with mutant forms of E-cadherin for potential N-glycosylation sites and evaluating its consequences on cancer cell
behaviour (in vitro and in vivo). This approach will allow us to identify for the first time the structural and biological
mapping of E-cadherin N-glycans in gastric tumor development and progression. We will further validate the findings by
analysing the pattern of expression of specific glycosyltransferases and their products in a set of human gastric
carcinoma cases displaying E-cadheri
1.2) In addition, and taking into consideration that E-cadherin is a pivotal molecular marker of Epithelial to Mesenchymal
Transition (EMT), we will continue to evaluate the role of glycosylation in general, and specifically on E-cadherin
regulation during EMT. We will further validate in vivo the role of N-acetylglucosaminyltransferase III (GnT-III)
glycosylation as a driver mechanism of EMT, as previously demonstrated (Pinho SS et al. PLoS ONE in press). 1.3) We will
continue to evaluate the role of glycosylation in the complex immune system network by addressing the impact of
glycosylation modification on T Cell Receptor (TCR) functions during the immunological response of Inflammatory Bowel
Disease patients.
2)
The group will continue to analyse the role that sialyltransferases play in the terminal glycosylation of proteins
important for the cancer cell behaviour. We will use previously established gastric cell lines expressing sialyltranferases
and displaying specific glycan phenotypes. We aim to identify protein carriers of these sialylated glycans by proteomic
analysis and perform in vitro and cell biology assays and in vivo experiments to characterise the functional role of these
glycans.
3)
The group will further clarify the mechanisms by which Galectin-3, an endogenous protein that recognises glycans as
ligands, regulates tumour progression and metastasis. The hypothesis to be tested is that the decreases of galectin-3
ligands in the extracellular matrix of malignant tumours may promote de-adhesion of cancer cells from primary tumour
sites and also progression on surrounding matrix with altered glycosylation, which favours invasion. The group will also
uncover the role of the microenvironment stimuli in differential/dynamic expression of galectin-3-binding sites, namely
due to sialylation alterations, in invading cells in CMMT, and perhaps more importantly to unravel potential inhibitors of
the interaction between galectin-3 and its ligands in order to impair metastatic dissemination of cancer cells.
We will study the cellular signaling underlying the activation of cell surface sialidases upon ligand binding to the receptor, namely
using EGF and EGFR, well known galectin-3 ligand , and evaluate its effects in galectin-3 binding to this receptor. We further intend to
impair galectin-3 mediated homo and heterotypic adhesion by hindering sialidase activity thereby preventing the unmasking of sialic
acid capping of galectin-3-ligands, using oseltamivir. We will assess its efficacy in vitro and also in vivo in a metastasis assay
conducted in nude mice, with special attention for events that take place at the invasion front. The viral sialidase inhibitor Tamiflu
(pure oseltamivir phosphate) was proven to be able to completely block human sialidase activity and is therefore a good candidate to
use in an anti-cancer sialidase activity trial in possible future clinical trials in dogs with CMMT.
The group will continue to develop glycoproteomic strategies for identification of biomarkers that can be used for cancer detection.
Various lines of research are going to be developed:
1)
The group will perform glycoproteomic strategies for characterization of the glycoproteome of cancer patients both in
tumour cells and serum in order to detect novel targets that can be applied in cancer diagnosis tests. The following
approaches will be used: a) Validation of the identified glycoproteins bearing cancer-associated carbohydrate antigens
will be performed by mass spectrometry; b) The glycoproteins identified by structural analysis will be prepared for
glycopeptides arrays as previously done for mucin glycoproteins based on recombinant MUC2, MUC5AC and MUC6
mucins. The glycopeptides of the new targets will be produced chemoenzymaticaly and printed on the arrays to screen
serum from patients with gastritis, intestinal metaplasia and gastric carcinoma. This approach aims at evaluating au
2)
The group will continue to prepare glycopeptide specific monoclonal antibodies with increased specificity for cancerassociated mucin glycoforms. a) Recombinant MUC2, MUC5AC and MUC6 proteins are being produced and glycosylated
in vitro with glycosyltransferases to produce cancer-associated glycoforms of the mucins. These mucin glycoforms are
being used to immunize mice in order to generate cancer-specific monoclonal antibodies. Preliminary data showed that
it is possible to generate a MUC2-STn specific immunoresponse in mice. Future efforts will be done to develop a
monoclonal antibody representative of this immuneresponse. Such novel antibodies may be useful in identifying
glycopeptides epitopes associated to gastric cancer patients.
CDX2 in intestinal differentiation and carcinogenesis
The general aim of this group is to uncover the pathophysiology of the gastric preneoplastic lesion intestinal metaplasia, focusing on
the transcription factor CDX2. We will continue studying CDX2 regulation and CDX2 novel targets with an emphasis on the
glycoproteome remodelling.
Following previous results we will continue studying CDX2 regulation by the BMP pathway. We will progress with this study by
developing an animal model with overexexpression of the pathway in the stomach and challenge it with H. pylori or other aggressive
agents to enhance a regenerative context, to try to induce IM. Furthermore, we will characterize this regulation in other in vitro
systems. In this regard, we will expand our study also to esophageal cell lines, where the regulation of CDX2 by the BMPs might also
be relevant, since the esophagus undergoes a transdifferentiation process involving intestinal metaplasia as well.
Following the recent identification of a post-transcriptional CDX2 regulatory mechanism involving the translation repressor MEX3A,
we will continue characterizing the cellular phenotype associated with MEX3A expression and CDX2 downregulation. For that we will,
in collaboration with Marc Billaud in Grenoble, search for novel MEX3A targets, using as first approach a bioinformatic screening. We
will further progress on the characterization of the cellular phenotype associated to MEX3A by characterizing the expression of
intestinal differentiation markers as well as stem cell markers, based on the data showing that MEX3A is preferentially expressed in
the crypt and bottom villus compartment of the intestine. We will also explore a putative function in polarity regulation, through
CDX2 (which is also known to regulate polarity) or other targets, to assess its relevance in normal intestine and in carcinogenesis.
Following the development of a strategy that enables the delivery of siRNAs directed to CDX2 in vivo, using a chitosan nanoparticle
approach ( in collaboration with INEB), we will test this system in vivo, using fluorescently labelled oligos and particles, to assess first
how the particles behave in the intestinal mucus layer. This will be performed in collaboration with Gunnar Hansson in Gotemburg.
Next we will assess CDX2 expression and the intestinal phenotype upon delivery of the particles in mouse intestine. After optimizing
44
the delivery program in intestine we will apply it to a mouse model with gastric intestinal metaplasia to assess reversion of the
lesion.
We have preliminary data generated by a PhD student, Rita Pinto, showing that CDX2 binds and transactivates enzymes associated
with an intestinal glycoproteome modification, namely ST6GalNAc-I and B3Gal-T5. For a more general view on CDX2 dependent
glycoproteome switch, engineered cells with Cosmc mutation (so-called simple cells) will be knocked-in for conditional expression of
CDX2 and for fluorescent tags linked to known targets (e.g. MUC2). A proteomic approach will be used to detect CDX2
glycoproteome dependent modifications. A preliminary study in mucinous carcinomas from different locations showed a highly
significant association between CDX2 expression and absence of expression of mucin MUC16, suggesting a repressor effect of CDX2
on MUC16 promoter. The newly developed MUC16 monoclonal antibody (and hopefuly new antibodies to be still developed) will be
used to study a large series of cases from different origins for CDX2 association.

Celso Reis, Hugo Osorio, Salomé Pinho, Fatima Gartner, Raquel Almeida, Leonor DavidWorkshop on Cancer Research:
biological and molecular basis Local: IPATIMUP Instituição: IPATIMUP/ICBAS Âmbito: Curso de formação contínua

Raquel Almeida, Celso Reis, Leonor DavidPrograma Doutoral de Medicina e Oncologia Molecular of the Medical Faculty of
the University of Porto.

Raquel Almeida, Celso Reis, Fatima Gartner, Leonor DavidPrograma Doutoral em Patologia e Genetica Molecular do
Instituto de Ciencias Biomedicas Abel Salazar

Raquel Almeida, Celso Reis, Leonor David, Salome Pinho, Hugo OsórioPhD program GABBA (Graduate program in areas of
Basic and Applied Biology) of the University of Porto

Raquel Almeida, Celso Reis, Leonor David, Hugo OsórioPrograma doutoral para medicos das Fundações Gulbenkian e
Champalimaud.

Raquel Almeida, Celso Reis, Leonor David.Programa Doutoral em Biomedicina

Fátima GärtnerPhD in Veterinary Science

Fatima Gartner, Raquel Almeida, Celso Reis, Leonor DavidMestrado em Oncologia Molecular do Instituto de Ciencias
Biomedicas Abel Salazar

Fátima GartnerMSc in Oncology
PRIZES

Bruno PereiraEMBL Corporate Partnership Registration Fee FellowshipTravel grant to attend the EMBO Conference on
Protein Synthesis and Translational Control (7-11 September 2011, Heidelberg, Germany)

Bruno PereiraCDX2 regulation by MEX3A1st Prize (ex-aequo) for the beest work on oncobiology at the I3S Meeting, May
2011 Povoa de Varzim, Portugal
INVITED TALKS

Celso A. Reis. Glycans mediating Helicobacter pylori adhesion to gastric epithelial cells. CFG Participating Investigators
Meeting. NIH - The Natcher Conference Center, NIH, Maryland, USA. 27/07/2011.

Celso A. Reis. Role of carbohydrates in gastric carcinogenesis. 9th International Meeting of the Portuguese Carbohydrate
Chemistry Group" and 5th Iberian Carbohydrate meeting. Vila Real, Portugal. 05/09/2011.

Celso A. Reis. Glycoproteomic strategies for characterization of glycosylation in cancer. Workshop on Proteomics Local:
IPATIMUP/CIIMAR Instituição: IPATIMUP/CIIMAR. CIIMAR. 20/05/2011.

Leonor David. Carcinogenese gástrica - um modelo de cancerização silenciosa. Jornadas Nacionais de Biomedicina.
Covilhã. 2011.

Salomé Pinho. Role of N-Glycosylation in the modulation of E-cadherin functions in cancer. FEBS Advanced Lecture Course
on Translational Cancer Research. Algarve, Portugal. 29/09/2011.

Maria Fátima Gärtner. Scientific Documents. Worshop do “Laboratório ao Papel". Instituto de Ciências Biomédicas Abel
Salazar da Universidade do Porto. 13-04-2011.
ORAL PRESENTATIONS

Hugo Osorio. 3 Oral presentations: Introduction to proteomics; Principles of MALDI-TOF/TOF MS and protein
identification; Protein quantification. Proteomics course: gel based protein separation by two-dimensional gel
electrophoresis and protein characterization by MALDI-TOF/TOF mass spectrometry. CIIMAR, Porto. 28/02/2011.

Santos A, Lopes CC, Marques RM, Amorim I, Frias C, Gärtner F, Matos AJF. MMP-9 immunoexpression in canine mammary
gland tumours: Relationship with poor prognostic factors and patient’s outcome. European Society of Veterinary
Oncology. Glasgow, Scotland. 24-26/3/11.
45
CANCER DRUG RESISTANCE
OBJECTIVES
Resistance of cancer cells to traditional chemotherapy and targeted therapeutics is both a major clinical problem and a scientific
challenge. Different approaches are currently being pursued with a view to overcoming this problem. Our group is mainly focused on
translating basic science findings into validation of potentially new molecular targets for cancer therapy, such as anti-apoptotic
molecules and some microRNAs, using several in vitro models for different cancer types. Also, in an attempt to counteract cancer
drug resistance, we are involved in testing newly synthesized compounds ("small molecules") in particular sets of cancer cell lines.
MAIN ACHIEVEMENTS
Understanding the role of microRNAs in Drug Resistance/Drug response in leukaemia cell lines
We have been investigating the role of selected microRNAs in cell growth, cell death and drug resistance/drug response, in acute
myeloid leukaemia. This work has been carried out in collaboration with Hospital São João and this project is financed by Fundação
Calouste Gulbenkian.
Our laboratory work has been focusing on miR-21 and we have found evidence of its involvement in cellular response to drugs
(manuscript in preparation). We have also published one review paper under this theme (Lima R.T. et al., Eur J Cancer 2011). In
addition, we have collaborated in a study in which we showed that miR-143 overexpression impaired growth of human colon
carcinoma xenografts in mice, with induction of apoptosis and inhibition of proliferation (Borralho P.M. et al., Plos One 2011).
Understanding the role of EBV proteins in drug response in Burkitt lymphoma cell lines
Epstein Barr Virus (EBV) is present in many tumours but it was not clear if it had an effect in drug response. We have investigated the
relevance of EBV proteins in drug response, in Burkitt lymphoma cell lines. We have described for the first time that EBV interferes
with the sensitivity of Burkitt Lymphoma cells to etoposide (Lima R.T. et al., J. Cell Biochem 2011). Furthermore, we showed that
treatment of EBV positive cells with doxorubicin caused more EBV reactivation than treatment with etoposide (Lima R.T. et al.,
Chemotherapy 2011).
Molecular targets involved in drug resistance in Cancer Stem Cells
We have been investigating the presence of targets related to drug resistance in Cancer Stem Cells. This work is a collaboration with
CEQUIMED-UP and with the Tumor Molecular Models Group at IPATIMUP. This project is funded by FCT (PTDC/EBBBIO/099672/2008) and the PI is Gabriela Almeida.
So far we have been successful at isolating and expanding putative CSCs from established pancreatic cancer cell lines, by cell sorting
with magnetic beads for specific CSCs membrane markers, although this is only efficient in certain cell lines. We are also performing
cell sorting by flow cytometry in order to improve putative CSC separation in other cell lines (pancreatic and lung cancer derived
cells). Additionally, we are carrying out various experiments to assess chemotherapeutic resistance in the putative CSC subpopulation when compared with the non-CSC population. We are also in the process of characterizing the two sub-populations,
regarding the presence of specific chemoresistance mechanisms, for the subsequent selection of appropriate targets to the
circumvention of resistance and incorporation into CSC-targeted nanoparticles, which are being developed in collaboration with
CEQUIMED-UP.
Role of P-gp and anti-apoptotic proteins in drug resistance
We have been interested in studying the role of antiapoptotic proteins, such as Bcl-2 or XIAP, and also of P-glycoprotein (P-gp) in
drug resistance. During 2011 we published one paper relating to the involvement of XIAP (and P-gp) in the resistance of leukemia
cells to Imatinib Mesylate. We showed that simultaneous targeting of P-gp and XIAP with siRNAs increases sensitivity of P-gp
overexpressing Chronic Myeloid Leukemia cells to imatinib (Seca H et al., Hematology 2011).
Identifying new P-gp inhibitors
Work carried out under this framework was initiated approximately 4 years ago as a joint project in collaboration with CEQUIMEDUP. This work aims at: i) the investigation of anti-Pgp activity in drugs known for other activities; ii) synthesis of molecules with dual
activity: anti-tumoral and anti-Pgp. An in silico screen of a library of molecules with a (thio)xanthonic scaffold (known to have antitumor activity) has been carried out (at the University of Madeira, under the supervision of Prof Miguel Xavier), to identify molecules
that inhibit P-gp. Synthesis of selected molecules was followed at CEQUIMED-UP and these compounds were all tested at IPATIMUP
for their anti-Pgp activity and cell growth inhibitory activity. Our work resulted in the identification of 16 new compounds with antiPgp activity, similar to that elicited by known inhibitors. From these compounds, 7 derivatives presented the ability to reverse
resistance to doxorubicin, in a resistant leukemia cell line which overexpresses P-gp , and 6 derivatives presented tumor cell growth
inhibitory activity with GI50 <10µM. Some of the results from this work were published (or accepted for publication) during 2011
(Palmeira et al., Chem Biol Drug Des 2011; Palmeira et al.,Biochem Pharmacol 2011; Palmeira et al., J Pharm Pharmaceut Sci 2012;
Palmeira et al., Curr Med Chem, in press).
Development of small molecules with antitumor potential
The area of development of novel small molecules has involved 2 parts during 2011: A) the screening of compounds with potential
antitumor activity, based on previous results from our collaborators at CEQUIMED-UP; B) the investigation of the cellular mechanism
of action of the best compounds. This work has been carried out as a collaboration with CEQUIMED-UP. This research area has been
funded by FCT (project having FFUP as the Proponent Institution, PI Prof Madalena Pinto, PTDC/SAU-FCF/100930/2008). We have
tested several xanthones and flavonoids and identified some compounds capable of decreasing cell growth and interfering with cell
cycle or apoptosis. Some of these results were published (or accepted for publication) during 2011 (Neves M.P. et al., Eur J Med
Chem 2011; Neves M.P. et al., Bioorganic and Medicinal Chemistry 2012; Neves M.P. et al., Chemistry and Biodiversity, in press;
Belaz K.R.A. et al., J Pharm Biomed Analysis, accepted for publication). In addition, we also collaborated with Universidade do Minho
(Prof Maria João Queiroz, through CEQUIMED-UP) and further identified compounds with potential antitumor activity (Queiroz M.J
46
.et al., Eur J Med Chem 2011; Abreu R.M.V. et al., Eur J Med Chem 2011). During 2011 we have also started to implement part B) of
this research area.
Searching for novel natural products with antitumor potential
Several studies have been carried out, mostly in collaboration with CEQUIMED-UP, CIIMAR and with Instituto Politécnico de
Bragança, in order to identify natural products with antitumor potential. Work under this area of research is funded by FCT (project
having Instituto Politécnico de Bragança as the proponent institution, PI Prof Isabel, PTDC/AGR-ALI/098402/2008) and by the
University of Porto.
Five publications resulted from this work during 2011 (Cazal C.M. et al., Anticancer Ag Med Chem 2010 (was published in 2011); Vaz
J.A. et al., LWT – Food Sci Technol 2011; Vaz J.A. et al., Food Chemistry 2011; Kijoa A. et al., Nat Prod Commun, 2011; Vaz J.A. et al.,
Food Chemistry, in press).
Robert Gordon University, Aberdeen, Scotland (Prof. Paul Kong).
Collaboration through the Erasmus student (Joanna Grabowska)
Queen’s University Belfast, Centre for Cancer Research and Cell Biology & Northern Ireland Cancer Centre, UK (Dr. Dean Fennell).
Collaboration through an FCT funded project, Reference PTDC/EBB-BIO/099672/2008 (Dr. Dean Fennel is consultant of the project)
and through the publication of one review paper.
University of Hawaii Cancer Center, Honolulu, HI, USA (Prof. Giovanni Gaudino).
Collaboration through the publication of one review paper.
University of Nebraska Medical Center (Prof. Arnold Angelo Rizzino).
Collaboration through an FCT funded project, Reference PTDC/EBB-BIO/099672/2008 (Prof. Rizzino is consultant of the project).
CEQUIMED-UP (Prof Madalena Pinto, Prof Emília Sousa, Prof Maria São José Nascimento, Prof Eugénia Pinto, Prof Maurício
Barbosa, Prof Cármen Maribel Teixeira, Dr Rosa Pereira).
Collaboration through co-supervision or training of PhD students, through several projects financed by UP and through three projects
financed by FCT (PTDC/SAU-FCF/100930/2008, PTDC/EBB-BIO/099672/2008 and PTDC/SAU-FAR/110848/2009).
Hospital São João (Prof José Eduardo Guimarães e Doutor Manuel Sobrinho Simões).
Collaboration through a PhD student (HS) and a Project financed by Fundação Calouste Gulbenkian.
Instituto Politécnico de Bragança (Prof Isabel Ferreira and Prof. Anabela Martins).
Collaboration through a PhD student and 2 projects (1 from UP and 1 from FCT: PTDC/AGR-ALI/098402/2008).
Universidade do Minho, Braga (Prof Maria João Queiroz).
Collaboration through CEQUIMED-UP and through several papers.
Universidade da Madeira, Departamento de Química e Centro de Química da Madeira (Prof Miguel Xavier Fernandes).
Collaboration through one PhD student and one project financed by FCT (PTDC/SAU-FAR/110848/2009).
REQUIMTE, Laboratory of Microbiology, Department of Biological Sciences of FFUP (Prof Lucília Saraiva).
Collaboration through one project financed by FCT (PTDC/SAU-FAR/110848/2009).
IBMC (Prof Arnaldo Videira e Doutora Andreia Fernandes).
Collaboration through 1 project financed by UP.
CIIMAR Laboratório Associado (Prof A. Kijjoa).
Collaboration through CEQUIMED-UP and one paper.
Research Institute for Medicines and Pharmaceutical Sciences - iMed.UL and Faculdade de Farmácia de Lisboa (Prof. Cecilia
Rodrigues).
Collaboration through one paper.
FUTURE RESEARCH
microRNAs with a role in cancer drug resistance
We have preliminary data which indicates that antimiRs targeting miR-21 increase the sensitivity of leukaemia cells (K562 cell line) to
etoposide and doxorubicin (Seca et al., Annals of Oncology 23, Supplement 1, 2012). It is our expectation to further investigate the
potential of these antimiRs to circumvent drug resistance.
Identification and validation of small molecule p53 modulators
With the identification of various p53 isoforms, several functions initially attributed to p53 are now believed to be shared by other
members of the p53 family. This brought new perspectives and expectations into the therapy of cancer. However, to date, no
pharmacological modulators of individual p53 isoforms have been described. We will collaborate with Prof. Lucília Saraiva to develop
small molecules modulators of p53 family proteins (project approved having ICETA-Porto/UP as the Proponent Instituion, PI Prof.
Lucília Saraiva, PTDC/SAU-FAR/110848/2009). This is a pluridisciplinar project, joining expertise in medicinal chemistry, in silico
screening, use of yeast as a model system and finally oncobiology.
Investigation of the mechanism of action of small molecules that are inducers of apoptosis in cancer cells
The aim will be to investigate the mechanism of action of three hit molecules from the CEQUIMED-UP library. This work consists of
the post-doctoral proposal of R.T. Lima. This proposal is partially integrated in a research project funded by FCT and already initiated
(PTDC/SAU-FCF/100930/2008), as collaboration between CEQUIMED-UP and IPATIMUP.
47

M Helena Vasconcelos. Programa Doutoral em Segurança e Saúde Ocupacionais, Faculdade de Engenharia da
Universidade do Porto

M Helena Vasconcelos. Programa Doutoral em Patologia e Genética Molecular, ICBAS, Module of Molecular Biology
Techniques.

Gabriela M AlmeidaGulbenkian PhD Programme 2011, Oncobiology module.

Gabriela M. AlmeidaGABBA 2011, Oncobiology Module.

M Helena VasconcelosMestrado em Genética Molecular, Departamento de Biologia, Universidade do Minho

Raquel T LimaMestrado de Análises Clínicas, ISCSN - Instituto Superior de Ciências da Saúde - Norte
PRIZES

Borralho PM, Simões AES, Gomes SE, Lima RT, Carvalho T, Vasconcelos MH, Castro RE, Rodrigues CMP."miR-143
overexpression reduces the growth of xenograft tumors from colon carcinoma cells, increasing tumor cell apoptosis and
decreasing proliferation"Co-authors of Best poster in “Basic research” at the XX Porto Cancer Meeting - “Drug Resistance
in Cancer: from biology to molecular targets and drugs”, IPATIMUP, Porto, Portugal, 28-29 April 2011. Presented by
Borralho PM.
INVITED TALKS

M Helena Vasconcelos. “Resistência a fármacos antineoplásicos”. Congresso “Oncologia” dos alunos do 5ºAno de Ciências
Farmacêuticas da Universidade da Beira Interior. Covilhã, Portugal. 06/01/2012.

Raquel T. Lima. "EBV: do beijo ao cancro". III Conferências – Microbiologia e Biologia do Cancro, Faculdade de Farmácia da
Universidade do Porto. Porto, Portugal. 30/11/2011.

Gabriela M. Almeida. "Overcoming drug resistance in cancer stem cells". VI Congresso Científico AEFFUP - Química
terapêutica e Novas Terapias. Porto, Portugal. 03/11/2011.

M Helena Vasconcelos. “Keynote Lecture”: “RNA interference in the viral infection”. 14th Annual Meeting of the European
Society of Clinical Virology. Madeira, Portugal. 23/09/ 201.

M Helena Vasconcelos. “Validation of therapeutic targets in cancer drug resistance”. Invited presentation on the occasion
of a Laboratory visit to “The Smurfit Institute, Trinity College”. Trinity College, Dublin, Ireland. 19/08/2011.

Josiana Vaz. “Antioxidantes e envelhecimento”. III SEMINÁRIO + Idade + Saúde - Contributos para a Saúde na População
Sénior. Bragança, Portugal. 04/06/2011.

Raquel T Lima. Avaliação de actividade anti-tumoral de produtos naturais: estado da arte. XII Semana das Ciências
Agrárias. Bragança, Portugal. 16/03/2011.
ORAL PRESENTATIONS

Calhelha RC, Ferreira ICFR, Abreu RMV, Vale-Silva LA,Pinto E, Lima RT, Alvelos MI, Vasconcelos MH, Queiroz MJRP .
Presented by Ricardo Calhelha. “Synthesis of aminodiarylamines in the thieno [3,2-b] pyridine series and effects on tumor
cell growth inhibition, cell cycle and apoptosis”. 3rd Congress of the Portuguese Society of Pharmaceutical Sciences and
9th Portuguese-Spanish Conference on Controlled Drug Delivery. Porto, Portugal. 15/10/2011.

Almeida AP, Macedo B, Cravo S, Dethoup T, Lima RT, Vasconcelos MH, Pinto M, Kijjoa A. Presented by AP Almeida. “The
marine fungi Eurotium cristatum: chemical study, evaluation of growth inhibition effect on human tumor cell lines and
development of HPLC analysis”. “3rd Congress of the Portuguese Society of Pharmaceutical Sciences and 9th PortugueseSpanish Conference on Controlled Drug Delivery”. Porto, Portugal. 15/10/2011.

Borralho PM, Simões AES, Gomes SE, Lima RT, Carvalho T, Castro RE, Vasconcelos MH, Rodrigues CMP (2011). Presented
by Borralho PM. "O microRNA-143 aumenta a apoptose e reduz a proliferação de células de cancro colorectal in vivo”. .
“Semana Digestiva 2011” organized by Sociedade Portuguesa de Gastrenterologia, Sociedade Portuguesa de Endoscopia e
Associação Portuguesa para o Estudo do Fígado. Estoril, Portugal. 02/06/2011.

Palmeira A, Paiva A, Choosang K, Seca H, Pakkong P, Sousa E, Pinto M, Vasconcelos MH. Presented by Andreia Palmeira.
"Antitumor activity of novel synthetic thioxanthonic derivatives mediating cell cycle arrest and apoptosis in human tumor
cell lines". New Indigo Workshop: Antiparasitic and antitumour drugs. Porto, Portugal. 09/09/2012.
48
PROTEOLYSIS IN DISEASES
OBJECTIVES
The group’s main objective and long term goal is to establish high throughput quantitative proteomics within Portugal and to
become competitive for EU funding in this area. The strategy to obtain this ambitious goal is to combine strong bioinformatics
expertise with skillful protein biochemistry and cell biology. The goal of establishing a team with the needed skills has already been
achieved in the two ongoing FCT funded projects PTDC/QUI-BIQ/099457/2008 (protein biochemistry and cell biology based) and
PTDC/EIA-EIA/099458/2008 (bioinformatics). Our research is focused on the development of novel mass spectrometric (MS) and
data analysis techniques for studying proteins and their post translational modification on challenging biological problems. The group
has experience and publications on quantitative proteomics targeting the following post translational modifications: phosphorylation
[1, 2], acetylation [3, 4], methylation [4], ubiquitination [5], GPI-anchors [6] and glycosylation [7, 8]. Furthermore ongoing projects
are targeting O-GlcNAc (FCT project, PTDC/QUI-BIQ/099457/2008), N- and C-terminomics (supported by Novo Nordisk) and
SUMOylation (Funded from external laboratory). Our research have already now caught the attention of important players in the
field and we have started and ongoing collaborations with “Professor Ole N Jensen, Protein Research Group, Odense Denmark”,
“Professor Akhilesh Pandey, Johns Hopkins University”, “Dr. Manuel Roderigez (CIC bioGUNE, Spain)”, “Dr. Sophie de Bentzmann,
France”, “Dr. Andrey Kajava, France” and we have further an ongoing collaboration with Dr. Albrecht Gruhler, Novo Nordisk,
Denmark on N- and C- terminomics. We have applied in the above mentioned collaborations, within the last year, for several
competitive international grants. The current effort is focused on obtaining two types of state of art mass spectrometers. One type is
mainly for explorative proteomics and this instrument can be an Orbitrap (Velos or Elite) or Synapt G2 S and this will be the first goal.
Next aim is to obtain a triple quadrupole type of instrument which will be important for attempting to translate our research,
together with our many clinical collaborators here in IPATIMUP, to diagnostic application.
References:
1.
Boeri Erba, E., et al., Quantitation of multisite EGF receptor phosphorylation using mass spectrometry and a novel normalization approach. J Proteome Res, 2007.
6(7): p. 2768-85.
2.
Fierro-Monti, I., et al., Quantitative proteomics identifies Gemin5, a scaffolding protein involved in ribonucleoprotein assembly, as a novel partner for eukaryotic
initiation factor 4E. J Proteome Res, 2006. 5(6): p. 1367-78.
3.
Beck, H.C., et al., Quantitative proteomic analysis of post-translational modifications of human histones. Mol Cell Proteomics, 2006. 5(7): p. 1314-25.
4.
Matthiesen, R., et al., VEMS 3.0: algorithms and computational tools for tandem mass spectrometry based identification of post-translational modifications in
proteins. J Proteome Res, 2005. 4(6): p. 2338-47.
5.
Lopitz-Otsoa, F., et al., Integrative analysis of the ubiquitin proteome isolated using Tandem Ubiquitin Binding Entities (TUBEs). J Proteomics.
6.
Omaetxebarria, M.J., et al., Computational approach for identification and characterization of GPI-anchored peptides in proteomics experiments. Proteomics, 2007.
7(12): p. 1951-60.
7.
Matthiesen, R., et al., Database-independent, database-dependent, and extended interpretation of peptide mass spectra in VEMS V2.0. Proteomics, 2004. 4(9): p.
2583-93.
8.
Hagglund, P., et al., An enzymatic deglycosylation scheme enabling identification of core fucosylated N-glycans and O-glycosylation site mapping of human plasma
proteins. J Proteome Res, 2007. 6(8): p. 3021-31.
MAIN ACHIEVEMENTS
The group proteolysis in diseases was formed with the central research line focused in the characterization of the role of proteolytic
processes in human health and disease, using a multidisciplinary approach able to combine the areas of evolutionary and population
genetics with molecular cell biology and MS-based proteomics. Precisely, we aim to uncover the basis of proteolytic phenotypes by
using different high throughput technologies, including next-generation sequencing and mass spectrometry. The first technology will
be used to characterize genetic variation in both random and diseased populations, thus facilitating the identification of variants with
predicted implications in gene expression and protein properties. A novel mass spectrometry technique will be used to explore in
vivo the diversity of proteolysis cleavage sites, thereby linking genotype and proteolytic phenotype. In addition, we will use
biochemical and molecular assays to validate specific candidate variants of disease, in which the role of post translation
modifications on the proteolytic phenotype may be also investigated. Overall, we will be able to identify, to predict and to evaluate
the effects of regulatory mutations in protein expression and of non-synonymous substitutions on protein structure, activity and
impact on post translation modifications.
Integrative analysis of the ubiquitin proteome isolated using Tandem Ubiquitin Binding Entities (TUBEs).
The successful use of proteasome inhibitors in clinical trials revealed the potential of the Ubiquitin Proteasome System for drug
development. Protein remodeling through ubiquitylation is known to regulate the stability and activity of essential cellular factors
through largely uncharacterized mechanisms. Here, we used Tandem repeated Ubiquitin Binding Entities (TUBEs) under nondenaturing conditions followed by mass spectrometry analysis to study global ubiquitylation events that may lead to the
identification of potential drug targets. Using this approach we identified 643 proteins including known and unknown ubiquitin
targets from human breast adenocarcinoma MCF7 cells treated with Adriamycin. Coherent with a global cellular response to this
genotoxic insult, cellular factors identified are involved in protein synthesis, cellular transport, RNA post-transcriptional modification
and signaling pathways regulating early stress responses. This includes components of large macromolecular complexes such as
subunits and regulators of the proteasome, supporting the use of this method to characterize networks of molecular interactions
coordinated by ubiquitylation. Further in vitro and in silico analysis confirmed that 84% of the total proteins identified here, are
ubiquitylated. More importantly the enrichment of known biomarkers and targets for drug development, underlined the potential of
this approach for the identification of this clinically relevant information.
49
Gains, losses and changes of function after gene duplication: study of the metallothionein family.
Metallothioneins (MT) are small proteins involved in heavy metal detoxification and protection against oxidative stress and cancer.
The mammalian MT family originated through a series of duplication events which generated four major genes (MT1 to MT4). MT1
and MT2 encode for ubiquitous proteins, while MT3 and MT4 evolved to accomplish specific roles in brain and epithelium,
respectively. Herein, phylogenetic, transcriptional and polymorphic analyses are carried out to expose gains, losses and
diversification of functions that characterize the evolutionary history of the MT family. The phylogenetic analyses show that all four
major genes originated through a single duplication event prior to the radiation of mammals. Further expansion of the MT1 gene has
occurred in the primate lineage reaching in humans a total of 13 paralogs, five of which are pseudogenes. In humans, the reading
frame of all five MT1 pseudogenes is reconstructed by sequence homology with a functional duplicate revealing that loss of invariant
cysteines is the most frequent event accounting for pseudogeneisation. Expression analyses based on EST counts and RT-PCR
experiments show that, as for MT1 and MT2, human MT3 is also ubiquitously expressed while MT4 transcripts are present in brain,
testes, esophagus and mainly in thymus. Polymorphic variation reveals two deleterious mutations (Cys30Tyr and Arg31Trp) in MT4
with frequencies reaching about 30% in African and Asian populations suggesting the gene is inactive in some individuals and
physiological compensation for its loss must arise from a functional equivalent. Altogether our findings provide novel data on the
evolution and diversification of MT gene duplicates, a valuable resource for understanding the vast set of biological processes in
which these proteins are involved.
Discussion on common data analysis strategies used in MS-based proteomics.
Current proteomics technology is limited in resolving the proteome complexity of biological systems. The main issue at stake is to
increase throughput and spectra quality so that spatiotemporal dimensions, population parameters and the complexity of protein
modifications on a quantitative scale can be considered. MS-based proteomics and protein arrays are the main players in large-scale
proteome analysis and an integration of these two methodologies is powerful but presently not sufficient for detailed quantitative
and spatiotemporal proteome characterization. Improvements of instrumentation for MS-based proteomics have been achieved
recently resulting in data sets of approximately one million spectra which is a large step in the right direction. The corresponding raw
data range from 50 to 100¿Gb and are frequently made available. Multidimensional LC-MS data sets have been demonstrated to
identify and quantitate 2000-8000 proteins from whole cell extracts. The analysis of the resulting data sets requires several steps
from raw data processing, to database-dependent search, statistical evaluation of the search result, quantitative algorithms and
statistical analysis of quantitative data. A large number of software tools have been proposed for the above-mentioned tasks.
However, it is not the aim of this review to cover all software tools, but rather discuss common data analysis strategies used by
various algorithms for each of the above-mentioned steps in a non-redundant approach and to argue that there are still some areas
which need improvements.
Differing evolutionary histories of WFDC genes
The whey acidic protein four-disulfide core (WFDC) gene cluster on human chromosome 20q13, harbors 17 small serine protease
inhibitor genes with roles in innate immunity, reproduction, and regulation of endogenous proteases. The WFDC cluster also includes
SEMG1 and SEMG2, which code for the major structural proteins of the semen coagulum. Previous studies proposed the WFDC
cluster as a prime example of rapid diversification and adaptive evolution in primates. Our work confirmed that even at short
timescales like those of modern humans, strong adaptive pressures are perceptible in the WFDC cluster. We validated three
independent signatures of natural selection in the WFDC cluster: one in Africans at SPINT4, another in Europeans at WFDC8 and
another one in Asians at SEMG1. Our experimental approaches included the resequencing of coding and non-coding regions of the
WFDC cluster in HapMap individuals. Using classic neutrality tests, we have identified distinct long haplotypes consistent with the
action of positive selection in SPINT4, WFDC8 and SEMG1. The most likely candidate variants include a haplotype configuration
[Ser73+98A] for SPINT4 that may simultaneously affect protein function and gene regulation; the -44A allele for WFDC8, which may
down-regulate gene expression by abolishing the binding site of two transcription factors; and Ser56 for SEMG1, which may modify a
nearby PSA-cleavage site and the antimicrobial potential of the semen. We proposed that WFDC8 has been shaped by short-term
balancing selection and SPINT4 and SEMG1 are under an incomplete selective sweeps. Such adaptive events are likely to be
correlated with an interdependence of variant fitness with different ecological variables.
Alpha-1-antitrypsin deficiency caused by Q0ourém
Alpha-1-Antitrypsin deficiency (AATD) is an autosomal-codominant disorder caused by different mutations in SERPINA1 gene. It is
one of the most common genetic diseases among European populations and it is characterized by reduced protein serum levels and
by unopposed elastase activity. This places affected individuals at higher risk of developing pulmonary disease in the adulthood.
AATD by null alleles is extremely rare and therefore, it is very difficult to address the clinical implications of SERPINA1 absence. This is
the case of Q0Ourém, a rare variant found in 41 patients (8 homozygous and 33 heterozygous) from four families living in Central
Portugal. Homozygous subjects were confirmed to have untraceable SERPINA1 levels and an extensive destruction of the alveolar
tissue. Heterozygous patients were found to have highly heterogeneous clinical profiles, supporting the hypothesis of additional
genetic and environmental factors playing a key role in the onset of disease. Using seven microsatellites flanking SERPINA1 and an
evolutionary approach we able to confirm the single origin of Q0ourém, in the Middle Ages, and to exclude the recent consanguinity
as a probable cause for severe AATD.
Contrasting features of SERPINA1and SERPINA2
The SERPINA1 and SERPINA2 genes are located on chromosome 14q32.1 in a cluster comprising nine additional members of the
SERPIN superfamily. With the exception of SERPINA1 and SERPINA2, which share a high sequence similarity (~80%) all other genes
are likely to represent ancient events of gene duplication. SERPINA2 is differently expressed from SERPINA1 and if translated it is
predicted to encode a SERPIN with a distinct inhibitory activity from SERPINA1. We have transfected mammalian cells lines to stably
express variants of SERPINA2 and SERPINA1 and we proved that SERPINA2 is translated into a 55kDa glycoprotein. Contrary to
SERPINA1, which is a secreted protein, we identified SERPINA2 as a non-secreted protein with a subcellular localization in the
endoplasmic reticulum. SERPINA1 misfolded variants showed a similar subcellular localization to SERPINA2 that could be linked to an
increased proteosome activity and protein polymerization. No evidences of protein degradation or polymerization were detected for
SERPINA2. Rates of molecular evolution support the conservation of SERPINA1 and SERPINA2 in primates, which is consistent with
the maintenance of two divergent functional proteins.
50
INDIGO project submitted
A network between John Hopkins University, US, INBIOMED, Spain and Institute of bioinformatics, India
The study of protein signalling (mainly O-GlcNAc) in M-phase of Human cell cycle by MS-based proteomcis and confocal
microscopy.
This is an on-going collaboration with Professor Ole N Jensen, Protein, Research Group, Odense, Denmark.
The human Whey-acidic-protein Four-Disulfide Core-domain (WFDC) cluster on 20q13 region: evolutionary history and role in
human health and disease.
Zelia Ferreira PhD project, co-supervised by Belen Hurle (Human Genome Research Institute at the National Institutes of Health NHGRI/NIH)
An evolutionary perspective into the role of kallikreins (KLKs) in male reproductive biology
Patrícia Marques PhD project, co-supervised by Victor Quesada (Department of Biochemistry and Molecular Biology, The University
of Oviedo)
FUTURE RESEARCH
Cancer membrane proteomics by quantitative MS
Cancer membrane proteomics by quantitative MS with the future aim of targeting membrane proteins as diagnostic markers using
SRM methods.
Quantitative protoemics of bacterial biofilms which is newly started collaboration with two France groups.
Exploring the diagnostic potential of proteolytic pathways
Exploring the diagnostic potential of proteolytic pathways with aim of targeting protease substrate as diagnostic markers using SRM
methods
Analysis of Dynamic changes in Post-translational modifications of Human Histones during cell cycle of Multiple Myeloma cell lines
Post-translational modifications role in cancer
Evaluation of role of proteolysis in the male reproductive system through the study of KLK (19q13.4) and WFDC (20q13) gene
clusters.
Many issues about the activities of KLKs and WFDCs still require clarification, including the contribution of genetic variation to male
reproduction and current patterns of health and disease. In this proposal, we aim to: 1) uncover the genetic variations in KLK and
WFDC clusters that to some extent underlie phenotypic variation in male reproductive function in both healthy and infertile
individuals; 2) evaluate the biological significance of both common and rare variants with predicted functional repercussions, either
beneficial or deleterious, while simultaneously contributing to better characterization of these genes; 3) address the long-term
evolution of KLK and WFDC to infer the importance of diverse reproductive factors and to detect major amino acid replacements
with high impact on protein activity.
Explore the contribution of other risk factors in Alpha-1-antitrypsin deficiency
Pulmonary and hepatic diseases associated to alpha-1-antitrypsin deficiency are clinically heterogeneous. While some individuals
with serum levels below the protective threshold never show disease symptoms others with less severe genotypes may have clinical
manifestation of the disease. We aim to: 1) identify protein modifications that may decrease the inhibitory capability of alpha-1antitrypsin or increase its polymerization and; 2) access the impact of other genes of proteolysis that might compensate for the low
levels of alpha-1-antitrypsin.

Rune Matthiesen GABBA

Ana Sofia Carvalho, Rune MatthiesenCiência Viva
INVITED TALKS

Rune Matthiesen. Computational methods for exploring protein isoforms based on MS data. SEPROT. Segovia, Spain.
2011.

Rune Matthiesen. Computational proteomicsin clinical research. ICAPII. Ourense, Spain. 2011.

Rune Matthiesen, Current MS technologies for biological research, Jornadas, Braga, 2012

Seixas S. Deficiência de Alfa1-Antitripsina: Espectro Mutacional, Diagnóstico Molecular e Casos Clínicos Associados a
Mutações Raras. Congress of the Portuguese Society of Pneumology. Porto, Portugal. 2011.

Seixas S. Examples of human adaptation in the proteolysis universe. Invited Seminar at Instituto Gulbenkian de Ciência
(IGC). Lisbon, Portugal. 2011.
ORAL PRESENTATIONS
Seixas S, Ivanova N, Ferreira Z, Rocha J, Victor BL. Loss and gain of function in human SERPINB11: an example of a gene under
selection on standing variation, with implications for host-pathogen interactions. European Society of Human Genetics Conference.
Amsterdam, Netherlands. 2011.
51
GENETIC DIVERSITY
OBJECTIVES
The group aims to establish a bridge between population genetics and clinical genetics. This symbiosis is of major importance when
analysing non recombining genetic markers, such as mitochondrial DNA (mtDNA) and Y-chromosome. For these markers it is
extremely difficult to disentangle between neutral and pathologic diversities because of its transmission in block and its haplotypic
distribution in human populations (many rare haplotypes). We will pursuit a detailed characterisation of worldwide genetic diversity
for the uniparental markers, and the design of studies to investigate complex phenotypes, namely fertility, longevity and cancer. New
developments in biostatistics and bioinformatics will be essential for an efficient evaluation of genetic diversity and mutation models
in neutral and pathological conditions.
In order to accompany the advances of the current genomic era, we are beginning the screening of genome-wide chips at a
population level, taking advantage of the powerful links between anthropology, bioinformatics, population genetics and clinical
genetics that the group has already established.
MAIN ACHIEVEMENTS
Genetics of the Arabian Peninsula
We described diversity for the most frequent mtDNA haplogroup in Arabian Peninsula, R0a, as well for the related haplogroup HV1,
concluding for major demographic expansions in the post-Glacial Maximum and important genetic exchanges between Arabia and
East Africa in the Holocene
Genetic diversity of traditional nomadic pastoralists from the Sahel
We analysed the maternal and paternal genetic diversity of traditional nomadic pastoralists from the Sahel, as well as their farmer
neighbours, showing that the former display a lower diversity, that there has been no substantial mating exchange between both
groups, and that the emergence of pastoralism might be earlier and/or demographically more important than the introduction of
sedentary agriculture in the African Sahel
Selection on mtDNA-encoded protein variants
We used detailed phylogenetic trees for human mtDNA, combined with pathogenicity predictions for each amino acid change, to
evaluate selection on mtDNA-encoded protein variants. Protein variants with high pathogenicity scores were significantly rarer in the
older branches of the tree, due to the effect of purifying selection. We found no measurable difference in this measure of purifying
selection in mtDNA across the global population. We obtained a list of all possible single amino acid variations for the human
mtDNA-encoded proteins with their predicted pathogenicity scores as a tool for assessing novel protein variations that are often
reported in patients with mitochondrial disease of unknown origin or for assessing somatic mutations acquired through aging or
detected in tumors
PopAffiliator - calculator for individual population affiliation in Eurasian, East Asian and sub-Saharan African groups, based on
genotype profiles for the common set of short tandem repeats (STRs) used in forensics
We developed a free online calculator named PopAffiliator (http://cracs.fc.up.pt/popaffiliator) for individual population affiliation in
the three main population groups, Eurasian, East Asian and sub-Saharan African, based on genotype profiles for the common set of
short tandem repeats (STRs) used in forensics. The calculator performs affiliation based on a model constructed by applying machine
learning techniques to a data set of approximately 15,000 individuals. The accuracy of individual population affiliation is
approximately 86%, showing that the common set of STRs routinely used in forensics provides a considerable amount of information
for population assignment, in addition to being excellent for individual identification.
Improving the Out-of-Africa model
We contributed to improve the Out-of-Africa model, by applying updated mutation rates and several statistical methods to complete
sequences of haplogroup L3, aiming to optimize the time estimation for the out-of-Africa migration, and concluding for an upper
bound at ~70,000 years, when climatic conditions were improving in Eastern and Central Africa. Thus, the out-of-Africa migration
seems to be related with climatic conditions instead of symbolically mediated behavior, which arose considerably earlier.
The Arabian Cradle: mitochondrial relicts of the first seps along the Southern Route out of Africa
The ‘‘southern coastal route’’ model predicts that the early stages of the modern human dispersal took place when people crossed
the Red Sea to southern Arabia, but genetic evidence has hitherto been tenuous. We have addressed this question by analyzing the
three minor west-Eurasian haplogroups, N1, N2, and X (85 Southwest Asian mtDNa complete genomes), which branch directly from
the first non-African founder node N, and coalesce to the time of the first successful movement of modern humans out of Africa, ~60
thousand years ago. The results show that these minor haplogroups have a relict distribution that suggests an ancient ancestry
within the Arabian Peninsula, and they most likely spread from the Gulf Oasis region toward the Near East and Europe during the
pluvial period 55–24 thousand ago.
Characterisation of the Neolithic in the Great Mediterranean
Martin Richards (Institute of Integrative & Comparative Biology, Faculty of Biological Sciences, University of Leeds, UK), Vincent
Macaulay (Department of Statistics, University of Glasgow, UK), João Zilhão (Department of Archaeology, University of Bristol, UK)
Characterisation of the settlement of Europe in the Upper Palaeolithic
52
Macaulay (Department of Statistics, University of Glasgow, UK)
Characterisation of the pre-history of Southeast Asia
Macaulay (Department of Statistics, University of Glasgow, UK)
Characterisation of the settlement of the Arabian Peninsula
Farida Alshamali, (Dubai Police General Headquarters) and Viktor Cerny (Institute of Archaeology of the Academy of Sciences of the
Czech Republic, Prague)
Complete mtDNA databases and genome-wide screenings applied to population genetics
Doron Behar (Rappaport Faculty of Medicine and Research Institute, Technion and Rambam Medical Center, Haifa, Israel)
Complete mtDNA databases and its application in clinical genetics
David C. Samuels (Center for Human Genetics Research, Department of Molecular Physiology and Biophysics, Vanderbilt University
Medical Center, Nashville, TN, USA)
Autosomal markers and worldwide population structure
Mathias Currat and Estella Poloni (Départment d’Anthropology et d’Ecologie, Université de Geneve, Switzerland)
Impact of human genetics on the outcome of Dengue infection
Anavaj Sakuntabhai and Richard Paul (Institut Pasteur, Paris, France) and colleagues of the EU funded project DENFREE
Network on the transatlantic slave trade
Thomas Gilbert (University of Copenhagen) and colleagues of the EU funded project EUROTAST
FUTURE RESEARCH
mtDNA haplogroup U8/K and the major processes in West Eurasian prehistory
The analysis of complete mtDNA genome in mtDNA haplogroup U8, and in particular its major subclade haplogroup K, is revealing
signs of the major processes in West Eurasian prehistory: the haplogroup as a whole originated ~50 ka, at the time of the first arrival
and spread of anatomically humans from Arabia, it diversified during the glacial period and spread with the Late Glacial, and it shows
further major expansion signals in Europe with the Neolithic and the spread of agriculture into Europe. Manuscript being drafted.
Neolithic genetic influence in the Great Mediterranean
We will evaluate the Neolithic genetic influence in the Great Mediterranean, based on complete mtDNA sequences belonging to
haplogroups J and T from the Near East, Europe and North Africa (around 200 new sequences). One manuscript accepted for
publication and another in the drafting stage.
Settlement of Europe in the Upper Palaeolithic
We will investigate the settlement of Europe in the Upper Palaeolithic, through the study of complete mtDNA sequences from the
Near East and Europe, belonging to haplogroup U (around 200 new sequences). Manuscript being drafted.
L0 and the place of origin of modern humans
Paleontological evidence places East Africa as the most probable location for the cradle of modern humans; by surveying the
complete mtDNA sequence of the oldest human lineage L0, we will show that the mtDNA phylogeny supports this view. Our study
will definitely establish that L0 could not have been originated in South Africa, where some of its branches are more frequent
nowadays, and is indeed the sign of the oldest human migration, which probably took place between 70 and 100 ka. First draft of the
manuscript finished.
Migration of African lineages into Arabia
We will investigate the African lineages L4 and L6, which been older than L3 and present in considerable frequency in Arabian
Peninsula, might be a sign of an older migration than the L3-derived out-of-Africa migration at 70,000 years ago; we are identifying
signs that these lineages were originated in East Africa and its introduction into Arabian Peninsula was a very recent one, most
probably due to slave trade mediated by Arabs. Data under statistical analysis.
Characterizing mtDNA diversity in Southeast Asia
If there is a region of the globe for which we need more information about the genetic diversity this is southeast Asia; we will
dedicate a big effort to the characterisation of mtDNA complete sequences in this geographic region aiming to shed light on its
settlement and posterior migrations due to climatic changes and Neolithic dispersion. We are beginning by haplogroup M7 and will
progress to other poorly characterized haplogroups.
Genome-wide screening in African Sahel
We have already raw data for 2,500,000 loci (Omni 2.5 Illumina array) in 139 individuals from several Sahel populations and are
waiting for the last 50 samples to be typed. This African region was the main corridor for migrations between west and east, and
towards north and south, being important for the introduction of agriculture and pastoralism, thus leading to the emergence of the
main African civilizations. It is also the region were certain phenotypes have evolved, as malaria susceptibility and food adaptations
(e.g. lactose intolerance). The high coverage of our chip will allow to gain insights on selection to these traits. Very recently the place
for the origin of the human species has been addressed in some genome-wide surveys, with indications that west Africa is also a
possible place of origin; we will address this issue also in this screening, contributing additional information to support or disregard
our observation from mtDNA of an origin in east Africa.
Genome-wide screening in Arabia
We will screen the 700,000 SNP chip from Illumina in populations from Arabia Peninsula and Near East, to complement our studies of
mtDNA in this region, said to be the first step of the out-of-Africa migration.
Genome-wide screening in Southeast Asia
Still in 2012, we will begin these screening in populations from southeast Asia, to be analysed in 2013
53
Y-chromosome screening in several regions of the globe
We are developing SNaPshot kits for typing Y-chromosome SNPs informative in typical haplogroups from the various geographic
regions we are investigating. The paternal information will complement the results we obtained for the maternal component of the
population.
Genomics and complex traits - dengue infection
As genomics is now in a boom phase, applying genome-wide screenings to enlarged population sets is in the order of the day. We will
analyze data from the Illumina 660WQuadv1 beadchip, containing 657,366 SNPs (single nucleotide polymorphisms) in individuals
with dengue infection from Thailand and Cuba. Cuba is a very interesting sample due to its high level of admixture between African
(not susceptible to dengue infection) and European (susceptible to dengue infection) gene pools. This line of investigation is included
in our participation in the EU funded project DENFREE, and we will receive students from Thailand and Cuba in our lab, to initiate the
analysis of data.
Setting up mtDNA complete sequencing by next-generation sequencing
We will begin to set up the complete sequencing of mtDNA by next-generation sequencing, by using the Iron Torrent platform
acquired by the services of IPATIMUP. This will be important to strengthen the collaboration we are initiating with Valdemar Máximo
and Jorge Lima, from the Cancer Biology group at IPATIMUP, in evaluating mtDNA mutations in cancer.
Online tools to automate analyses of the mtDNA tree based on the complete genome
We will develop online tools to automate analyses of the mtDNA tree based on the complete genome, having in mind clinical
applications such as the evaluation of the pathogenicity potential of mutations. We have the close collaboration of colleagues from
the Faculty of Engineering, University of Porto.
Release software for founder analysis
We will make available to the community our software for founder analysis. This analysis allows to estimate the time for migration of
lineages from a source to a sink populations. This software was developed by the Master student in Informatics and Computing
Engineering (Faculty of Engineering, University of Porto) Marco Alves, who finished his thesis in July 2011.
Evaluation of selection on mtDNA-encoded protein variants and calibration of the mutation rate in several mammalian species
We will publish the results on the evaluation of selection on mtDNA-encoded protein variants and calibration of the mutation rate in
several mammalian species (chimpanzee, dog, mouse, rat, cow and orca), performed by the Master student in Bioinformatics
(University of Minho) Diogo Abrantes, who finished his thesis in December 2011.

Luisa Pereira. Programa Doutoral e Mestrado de Investigação Biomédica, Faculty of Medicine University of Coimbra

Luisa Pereira, Pedro SoaresSupervision and co-supervision of the thesis in the Integrated Master in Informatics and
Computing Engineering “Library of software for analysis in Population Genetics”. Student: Marco Alexandre do
Nascimento Alves. Faculty of Engineering, University of Porto.

Luisa Pereira, Pedro SoaresSupervision and co-supervision of the thesis in the Master of Bioinformatic “Searching for
purifying selection in the mitochondrial DNA of various mammal species”. Student: Diogo Abrantes. School of Engineering,
University of Minho.
INVITED TALKS

Luisa Pereira. The voyages of human genes. Stars and Stones: Voyages in Archaeoastronomy and Cultural Astronomy – A
meeting of different worlds. An International Conference on Archaeoastronomy and Ethnoastronomy. SEAC 2011. .
Universidade de Évora. 20/09/2011.

Luisa Pereira. Role of mtDNA as a genetic marker. II Advanced Course and International Workshop on Clinical Case
Reports “The second genome: mitochondrial genetics – from genotype to phenotype and clinical expression.”. Faculdade
de Medicina, Universidade de Coimbra, Pólo III. Coimbra. 20/01/2011.
ORAL PRESENTATIONS

Luisa Pereira. Mitochondrial DNA genomics: measuring selection on humans and implications in clinical genetics. . 2nd I3S
Scientific Retreat. Póvoa de Varzim. 05/05/2011.
54
TUMOR MOLECULAR MODELS
OBJECTIVES
The major research interest of the group is to decode the molecular models beneath the initiation, progression and resilience of
epithelial tumors. Our focus are cell membrane proteins which are key factors in these processes with relevance on cell-cell cross talk
and external stimuli integration. MUC1 glycoprotein constitutes our elective target due to the multiple functional roles and the
frequent alterations of the molecule observed in several tumor types. We aim to identify the relevance of MUC1 in oncogenic
signaling and drug resistance phenotype of cancer cells. The long-term objective is to develop MUC1 comprehensive models critical
for the development of new diagnostic and/or therapeutic strategies that effectively overcome current limitations on tumor
detection and therapy.
MAIN ACHIEVEMENTS
MUC1 signaling in gastric cancer
MUC1 is a major component of the stomach mucus layer that modulates interactions between the epithelium and external factors.
MUC1’s highly conserved cytoplasmic domain (MUC1-CD) has been recently reported to be involved in cell signaling processes in
different tumor models. Using coimmunoprecipitation/immunoblotting and Proximity Ligation Assay (PLA) we proceed with the
dissection of MUC1-mediated signaling pathways in gastric cancer cells.
We found that MUC1 interacts with several members of MAPK signaling cascade (EGFR, Grb2, B-RAF and ERK1/2) and also B23,
CDK1/2, E-cadherin and ß-catenin. These interactions were not observed in normal gastric tissue samples.
We found that MUC1 conditions phosphorylation of specific activity-related phosphorylation sites of ERK1/2, B23 and CDK1/2.
We showed that binding of Helicobacter pylori pathogenic strain HP26695 to MKN45 gastric carcinoma cells increases
phosphorylation of ERK1/2 in a time dependent manner.
These observations proved an extensive involvement of MUC1 in gastric cancer signaling pathways namely EGF/MAPK and ß-catenin
pathways. These findings reinforce the relevance of MUC1 in gastric carcinogenesis not only on the perspective of H.pylori adhesion
but also on the putative oncogenic signaling triggered by the infection. These results were presented at the "11th International
workshop: Mucins in Health and Disease, 2011, Cambridge, UK" (“MUC1 and MAP kinases pathway – new insights into the oncogenic
signalling in gastric cancer cells”), and at the "Molecular Mechanisms in Signal Transduction and Cancer Course, 2011, Spetses,
Greece" (“MUC1 interaction with cell signaling molecules in gastric carcinoma cells”).
MUC1 in pancreatic cancer stem cells
MUC1 is overexpressed in more than 80% of pancreatic tumors, correlating with tumor initiation, tumor progression and poor
survival of cancer patients. MUC1 highly conserved cytoplasmic tail (MUC1-CT) participates in several oncogenic signaling pathways.
We investigated MUC1 expression in pancreatic cancer stem cells (PCSC) and we characterized MUC1 involvement in oncogenic
signaling pathways of PCSC.
We characterize the expression of MUC1-CT and oncogenic signaling transducers (EGFR, Erk1/2, PKCd, GSK3ß and GRB2) as well as
MUC1-ß-catenin association in putative PCSC subpopulations (CD133+) from Capan2 and HPAFII pancreatic cell lines. MUC1-CT, EGFR
and PKCd expression levels are increased in the CD133+ subpopulation while a decreased expression of Erk1/2 and GSK3ß was
observed.
Furthermore we showed an increased interaction between MUC1-CT and ß-catenin in CD133+ subpopulation, which is in accordance
with the expression patterns of EGFR, PKCd and GSK3ß. MUC1 phosphorylation promoted by EGFR and PKCd is known to increase
MUC1-CT/ß-catenin association while phosphorylation promoted by GSK3ß produces the opposite effect: EGFR and PKCd are
upregulated while GSK3ß is downregulated in the CD133+ subpopulation. This MUC1-CT/ß-catenin association might interfere with
ß-catenin activity as a transcription factor and/or prevents ß-catenin participation in other signaling pathways, thus contributing to
the increased tumorigenic potential of PCSC. MUC1 seems to be a relevant player for PCSC biology and thus might constitute an
elective target to novel pancreatic cancer therapies.
These results were presented at “Stem Cells, Cancer and Metastasis - Keystone Symposium", Colorado, USA(“Characterization of
cancer stem cells involvement in pancreatic cancer resistance to chemotherapy”) and "1st Meeting of FMUP PhD students", Porto,
Portugal, (“MUC1 mucin in pancreatic cancer stem cells”).
MUC1 splice variants relevance for pancreatic cancer cells phenotype
Eighty percent of pancreatic tumors present an overexpression of MUC1 which has been associated with poor prognosis. The MUC1
gene encodes a large extracellular domain with a tandem repeat region, a self-cleaving domain, a transmembrane domain and a
highly conserved cytoplasmic domain (MUC1-CD). Nonetheless, a variety of alternative forms can be generated by alternative
splicing and some have been recently described in human embryonic stem cells. Considering our preliminary results that showed
that MUC1 is over-expressed in PCSC, our hypothesis is that MUC1 alternative splice variants play a relevant role in the
tumorigenesis of pancreatic tumors, namely in PCSC biology.
During this year, using the pancreatic cancer cell line S2-013 which has overexpression of MUC1/Y, MUC1/X and MUC1/Z, spliced
variants that lack the tandem repeat region, and MUC1/SEC isoform, which lacks the cytoplasmic tail and the transmembrane
domain, we have identified, by PLA (Proximity Ligation assay), different interaction levels between MUC1 and important proteins
involved in the MUC1 signaling pathway such as EGFR, ß-catenin and p53. Furthermore, we have identified, using the same
technique, the interaction between MUC1-CD133 and MUC1-LGR5, proteins that have been described as cancer stem cell markers.
These results were presented at "11th International workshop: Mucins in Health and Disease, 2011, Cambridge, UK" ("MUC1 Directly
Binds p53 to Regulate Gene Expression").
55
Michael Anthony Hollingsworth. Eppley Institute – University of Nebraska Medical Center - UNMC .
MUC1 involvement in signaling pathways. Prof. Hollingsworth is also the co-supervisor of PhD Students Natália Costa and Andreia
Sousa.
Angie Rizzino. Eppley Institute - UNMC.
On going collaboration for optimization of in vitro models for isolated cancer stem cells.
Michele Ouellette. Eppley Institute - UNMC.
On going project of immortalization of gastric normal cells.
Pankaj Singh. Eppley Institute - UNMC.
On going collaboration for the identification of novel therapy targets in long-term gemcitabine-resistant pancreatic cancer¿ cells.
Paul Grandgenett. Eppley Institute - UNMC.
On going project for the evaluation of MUC1 isoforms impact in pancreatic cancer cell biology.
Ola Soderberg. University of Uppsala.
On going collaboration on the optimization of Proximity Ligation Assay for MUC1-mediated signaling pathways dissection in gastric
cancer.
Paula Alves. Animal Cell Technology Group - ITQB – Universidade Nova de Lisboa.
Ongoing collaboration for optimization of large-scale expansion of pancreatic cancer stem cells (Bioreactors) using microcarriers.
Manuel Coelho. Chemical Engineering Group – Faculdade de Engenharia da Universidade do Porto (FEUP).
Ongoing collaboration for in vitro evaluation of anti-tumor activity of functionalized nanoparticles using cancer cell lines.
Patricia Mesquita. Instituto Nacional de Recursos Biológicos, I.P. (INRB/MADRP).
On-going collaborative project on MUC1 transcriptional regulation in bovine endometrium cells by the maternal hormones
progesterone and estrogen and by the embryo - a crucial process on implantation.
Subramanian Viswanathan. REQUIMTE - Instituto Superior de Engenharia do Porto.
Development of MUC1 based nanobiosensors for pancreatic cancer early detection in serum samples.
C. Teixeira : Omaha, NE, EUA
Deslocação para o Eppley Institute, Omaha, NE, EUA no período de 12 de Maio a 13 de Julho.
FUTURE RESEARCH
MUC1 - exploratory studies for the development new diagnostic and therapeutic tools
We plan to strength the interaction with FEUP and REQUIMTE collaborators in order to proceed with the evaluation of MUC1-based
strategies for early detection (nanobiosensors) and therapy (MUC1-functionalized nanoparticles).
MUC1 impact in pancreatic cancer stem cells phenotype
We envision MUC1 oncoprotein as an elective target to tackle pancreatic cancer resilience to current therapies. We will evaluate
how MUC1 expression levels, alternative splicing variability (MUC1 isoforms) and post-translational modifications (e.g. glycosylation)
condition differentiation and drug-resistance phenotype of PCSC.
MUC1 signaling in gastric cancer cells
We will proceed with further dissection of MUC1-mediated oncogenic signaling pathways in gastric cancer cells. Considering our
results showing the involvement of MUC1-CD in oncogenic signaling pathways of gastric cancer cells, we will evaluate how MUC1
variability (VNTR) and post-translational modifications (e.g. phosphorylation) may condition these signaling pathways.

Andreia Sousa. Programa Doutoral em Biomedicina da Faculdade de Medicina da Universidade do Porto. Título da tese:
“Relevance of MUC1 splice variants for pancreatic cancer stem cells phenotype”

Ana Cristina Barros. Programa Doutoral em Ensino e Divulgação das Ciências (especialização em Divulgação das Ciências)
da Faculdade de Ciências da Universidade do Porto. Título provisório da tese: "A comunicação em Saúde: uma nova
abordagem na prevenção do cancro".

Natália Costa. Programa Doutoral em Biomedicina da Faculdade de Medicina da Universidade do Porto. Título da tese:
“Impact of MUC1 mucin in gastric carcinogenesis".

Filipe Santos Silva. PhD program GABBA (Graduate program in areas of Basis and Applied Biology) - University of Porto.
Oncobiology Module.

Filipe Santos SilvaPhD program for Medical doctors - Gulbenkian and Champalimaud Foundations. Oncobiology Module.
56
POST-GRADUATION UNIT
OVERVIEW
In 2011 several activities were developed by the Post-Graduation unit of IPATIMUP. These activities included internal and external
modules for Post-graduation programs.
HIGHLIGHTS
Module ONCOBIOLOGY
Module: ONCOBIOLOGY Local: IPATIMUP Institution: Gulbenkian/Champalimaud Program: The Programme for Advanced Medical
Education Students: 10 Date: 10-14 January 2011
Workshop on Cancer Research: biological and molecular basis
Módulo: Workshop on Cancer Research: biological and molecular basis Local: IPATIMUP Instituição: IPATIMUP/ICBAS Âmbito: Curso
de formação contínua Número de alunos: 20 Data: 16-20 May 2011
ONCOBIOLOGIA
Módulo: ONCOBIOLOGIA Local: IPATIMUP Instituição: Faculdade de Medicina do Porto Âmbito: PD em Medicina Oncologia
Molecular Número de alunos: aprox. 12 Datas: 21, 23, 25, 28 March and 1 April 2011.
Genética Humana Aplicada
Módulo: Genética Humana Aplicada Local: GABBA Instituição: UP Âmbito: Programa Graduado em Biologia Básica e Aplicada - da
Universidade do Porto Número de alunos:12
Workshop on Proteomics
Módulo: Workshop on Proteomics Local: IPATIMUP/CIIMAR Instituição: IPATIMUP/CIIMAR Âmbito: Curso de formação contínua
Número de alunos: 20 Data: 16-20 May 2011.
57
OUTREACH ACTIVITIES
58
SCIENCE DIFFUSION
OVERVIEW
The Science Diffusion Unit aims to promote scientific culture, interacting whether with schools or with the community. Thus, during
2011 the Science Diffusion Unit has developed/been involved in the following activities/projects:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
"Laboratório Aberto"
"Porto de Crianças"
"Mostra UP"
"VI Feira da Ciência – Vila de Conde"
"Ciência Viva no Verão"
IPATIMUP's Day
"Noite dos Investigadores"
"Escola das Ciências da Vida e Saúde"
School meetings
“Entrelaçar” project
"Traz um amigo também"
"Segunda há Ciência"
HIGHLIGHTS
Laboratório Aberto
In 2011 the objectives of the "Laboratório Aberto" have been met. The "Laboratório Aberto" has received about 5,000 students from
around the country that performed hands-on practical activities.
"Porto de Crianças"
In 2011, the protocol with the City Council of Porto, which was about to end, was maintained meeting the project objectives.
Four schools benefited from this project which contemplated 64 sessions in the classroom, with the participation of 83 students in
4th grade.
"Ciência Viva no Verão"
The project received two more students than last year (32 total) and there was also an increase in funding.
ACTIVITY STATISTICS
District
Aveiro
Braga
Castelo Branco
Coimbra
Leiria
Porto
Setúbal
Viseu
TOTAL
Students
616
511
29
93
171
3651
72
43
5186
Teachers
52
36
3
10
16
371
6
4
498
Total
668
547
32
103
187
4022
78
47
5684
Laboratório Aberto visitors
1.000
750
500
250
0
Jan Feb Mar Apr May Jun
Jul
Ago Sep Oct Nov Dec
QUALITY CONTROL
Laboratório Aberto
At the end of each visit, students and teachers filled out a satisfaction survey of the activities, with the following topics:
1. Satisfaction of the activities presented;
2. Appropriate scientific language;
3. Scientific rigor;
4. Would you return to "Laboratório Aberto"?
Nearly 100% of people have given maximum rating on the topics asked.
59
PUBLIC AWARENESS OF CANCER
OVERVIEW
Public Awareness of Cancer Unit is focused on the research and development of new strategies for health education among students,
health professionals and general audiences.
HIGHLIGHTS
Projects (multimedia and special education areas):
a) “Prevention and early diagnosis of cancer and precancerous lesions of cervix, stomach, breast and thyroid –
CancerMobile” (Funded by EEA),
b) “Development of a medical information system about Hereditary Breast and Colorectal cancer” - (Funded by Harvard
Medical School Portugal Program),
c)
“Cancer: Educate to Prevent” – (Funded by The High Comissioner for Health).
d) “Development of a model of inclusive education of science in a population visually impaired students”- (Funded by
Calouste Gulbenkian Foudation).
e) “Life MOVES – active aging program” – collaboration with Piaget Institute.
Development of products:
a) MICe 2.0 – new version of this educational software (virtual microscope), with new activities and redesigned to cope with
the capacity of students personal computer (Computador Magalhães).
b) In Vivo - short documentaries about cancer prevention.
c)
CancerMobile – cancer prevention sessions designed to specific audiences.
d) VIP-Edit – video production of lab research protocols.
Workshop organization
“Inclusive Science – Teaching science to blind or visually impaired students”. Escola Secundaria Rodrigues de Freitas.
Porto, Portugal. (Funded by Calouste Gulbenkian Foundation).
INVITED TALKS
Santos Silva F. “Development of a medical information system about hereditary breast and colorectal cancer”. Harvard Medical
School Portugal Program – 2nd Annual retreat. Lisboa, Portugal. 2011.
Carvalho L, Santos Silva F. “Teaching science to pupils who are blind or visually impaired: lessons for teachers of sighted pupils”.
Institute of Education, University of Reading. Reading, UK. 2011
CONFERENCES AND MEETINGS
Carvalho L. “1st European Edition of the FIRST IV project – Scientific Teaching”. CIBIO. Porto, Portugal.
Lamas S. “I Congresso Nacional de Prevenção Oncológica e Direitos dos Doentes”. Liga Portuguesa Contra o Cancro. Porto, Portugal.
Marcos N. “Pain management project”. Health and Wellness Innovations- 2012. MIT Lab Media. Boston, USA.
60
IPATIMUP DIAGNOSTICS
OVERVIEW
In 2011, IPATIMUP Diagnostics, consisting of three departments - Pathology (LAP), Genetic Diagnosis (LDG), and Parentage testing
and Genetic Identification (LPIG) - made a considerable effort in raising the quality standards and successfully achieved CAP
accreditation and ISO 9001:2008 certification in all areas, thus accomplishing one of the main goals outlined from the fusion of the
three areas in 2010.
HIGHLIGHTS
CAP accreditation and ISO 9001:2008 certification was successfully maintained by the Pathology department (LAP) and extended to
Genetic Diagnosis (LDG) and Parentage Testing and Genetic Identification (LPIG) areas.
ACTIVITY STATISTICS
Exams
LAP
LDG
LPIG
Total
12478
Histology
894
Cytology (includes 2862 cases of FNA cytology)
10069
Molecular Pathology
823
Consultations
239
Total
3627
Tumour mutation screening
2080
Genetic Diagnosis
1547
Total
200
Genetic Characterizations (including lineage markers)
111
Parentage investigations and genetic profile comparisons (sample/individual)
89*
* each exam involves analysis of two or more samples/persons.
Consultations
Brazil
25
Ireland
6
Turkey
5
USA
6
United Kingdom
6
Norway
10
Germany
1
Mozambique
17
Portugal
73
Canada
4
Switzerland
5
Jordan
4
Spain
11
Romania
5
The Netherlands
4
Algeria
34
France
13
Greece
4
Belgium
6
QUALITY CONTROL
1. LAP
Internal Quality Control
The main findings, compared with the last 3 years, were:
2009
2010
2011
Total nº of cases
10.883
11.746
12.478
Cases reviewed
501
470
479
Discordant values:
Critérios
2009
2010
2011
Identification of specimen, archive and macroscopy
3.9%
1.06%
0.0%
Diagnosis
0.2%
0.2%
0.0%
Coding
0.5%
0.0%
3.5%
(17/479)
61
In 2010 the “turn-around time” (TAT) was the following:
Histological Exams: 75,63% of reports are sent in 2 working days.
Cytological Exams: 92,82% of reports are sent in 2 working days.
Screening cytologies: 100% of reports are sent in 7 working days.
The main results for the Gynecological Citology quality control analysis were:
2009
2010
2011
Total cases
5129
6733
6977
Reviewed cases
1013
1253
1281
2009
2010
2011
Concordance
between
pathologist and
cytotechnician
896
(88, 5%)
1150
(91.78%)
1204
(93.99%)
Discordance
between
pathologist and
cytotechnician
117
(11, 5%)
103
(8.22%)
77
(6.01%)
The total amount of unsatisfactory cases for analysis was 0,85% (0.59% in 2010, 0,75% in 2009).
ASCUS/ACG were diagnosed in 136 cases with a ASCUS/Lesion reason of 2,23 (2,57 in 2010, 2,67 in 2009).
External Quality Control
Apart from participating, with concordance, in all CAP Proficiency Tests, we continue to positively
participate in external quality control programs for imuno-histochemical techniques of UK-NEQAS
and the Quality Program of the Brazilian Society of Pathology (PIQ). All these activities are registered according to our procedure PR
MED-05.
2. LDG
Participation in the 2011 CAP biannual MGA Proficiency Tests with a concordance 100%
Participation in the Regional KRAS EQA scheme 2011 with a genotype score 100%.
These data can be consulted at
http://kras.eqascheme.org/info/public/eqa/previous_participants.xhtml
3. LPIG
Internal Quality Control
The main features comprising internal quality control are measured according to PR.QUA.10 established in 2011. The main finding
concerns the overall turn-around time (Tat) which was:
- 80,75% exams with simple reference samples were sent in 10 working days
- 62,75% exams with complex reference samples were sent in 20 working days
- 87,50% exams with limit samples were sent in 30 working days
All the other quality control measures are above the goals established as acceptable.
- Participation in the 2011 Quality Control Annual Exercise (Paternity and Forensics) of the GHEP-ISFG (Spanish and Portuguese
Group of the International Society for Forensic Genetics). This year the quality control program consisted of four exercises divided
into two categories:
Basic Module: Parentage and Forensic exercises. 100% concordance in both exercises.
Advanced Module: Parentage and Forensic exercises. 100% concordance in Forensic exercise; Parentage exercise not
evaluated due to lack of consensus.
Participation in the 2011 CAP triennial PARF Proficiency Tests. Concordance: PARF-A 100%, PARF-B 98,6% and PARF-C
97,1%. Discrepancies were observed in likelihood ratio results due to the use of our in-house allele frequency database.
Avoiding this type of discrepancy in the future implies application of frequency data from a US database used by the
majority of participating US laboratories.
62
OTHER ACTIVITIES
Training
Name
Period
Training
Current
situation
Dr. Sílvio Vale, Anatomical Pathology Intern, INCA, Rio de Janeiro, Brazsil
01/01/2011
31/01/2011
-
Anatomical
Pathology
Cytopathology
and
Concluded
Dr. Gilberto Uemura, Mastology Professor, UNESP, São Paulo, Brazil
01/02/2011
31/03/2011
-
Anatomical
Pathology
Cytopathology
and
Concluded
Dr. Giovanna de Sanctis Callegari, Anatomical Pathology Intern, Faculty of Medicine, São
Paulo University, Brazil
01/06/2011
29/07/2011
-
Anatomical
Pathology
Cytopathology
and
Concluded
Dr. Mariana Pimentel Pastor, Anatomical Pathology Intern, Faculty of Medicine, Rio Preto,
São Paulo, Brazil
01/06/2011
29/07/2011
-
Anatomical
Pathology
Cytopathology
and
Concluded
Dr. Ana Karla Araújo Cavalcanti de Albuquerque, Anatomical Pathology Intern, INCA, Rio
de Janeiro, Brazil
12/09/2011
11/11/2011
-
Surgical
Pathology
Cytopathology
and
Concluded
Dr. Beatriz Frolini Palu , Anatomical Pathology Intern, Campinas University, Campinas, São
Paulo, Brazil
04/10/2011
04/11/2011
-
Surgical
Pathology
Cytopathology
and
Concluded
Dr. Mariangela Crispiano Barata, Anatomical Pathology Intern, UNIFESP,São Paulo, Brazil
04/11/2011
04/12/2011
-
Aspiration Cytology
Concluded
Dr. Andreia Filipa Melo, Forensic Genetics Masters Student, FCUP, Porto, Portugal
01/09/2011 –
Forensic Genetics
Ongoing
Dr. Georges Aftimos, INP, Baabda, Libano
21/03/11 – 25/03/11
Molecular Pathology
Concluded
Dr. Wafa Elbjeirami, KHCC, Amman, Jordânia
21/03/11 – 25/03/11
Molecular Pathology
Concluded
Dr. Razan Alajoleen, Amman, Jordânia
21/03/11 – 25/03/11
Molecular Pathology
Concluded
Dr. Nidáa Ababneh, Amman, Jordânia
21/03/11 – 25/03/11
Molecular Pathology
Concluded
Dr. Roubi Obeid, KHCC, Amman, Jordânia
21/03/11 – 25/03/11
Molecular Pathology
Concluded
Tânia Ribeirinha, ESTSP, Porto
1/03/2011
31/03/2011
–
Molecular Genetics
Concluded
Gisela Magalhães, ESTSP, Porto
1/04/2011
31/04/2011
–
Molecular Genetics
Concluded
PUBLICATIONS
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Abelha FJ, Fernandes V, Botelho M, Santos P, Santos A, Machado JC, Barros H. Apolipoprotein E e4 allele does not
increase the risk of early postoperative delirium after major surgery. Journal of Anesthesia (in press).
Albergaria A, Ricardo S, Milanezi F, Carneiro f, Amendoeira I, Vieira D, Teijeiro JC, Schmitt F. Nottingham Prognostic Index
in Triple-Negative Breast Cancer: a reliable prognostic tool? BMC Cancer DOI 10.1186/1471-2407-11-299, 2011.
Alvarenga AC. Paravidino PI, Alvarenga M, Dufloth R, Gomes M, Zeferino LC, Schmitt F. Expression of CK19 in invasive
breast carcinomas of special histological types: implications for the use of one-step nucleic acid amplification. J Clin Patol
64:493-497, 2011.
Gelabert-Besada M, Alves C, Ferreira S, García-Magariños M, Gusmão L, Sánchez-Diz P (2011) Genetic characterization of
Western Iberia using Mentype(®) Argus X-8 kit. Forensic Sci Int Genet. 6:e39–e41.
Gerhard R, Costa JL, Schmitt F. Benign and malignant apocrine lesions of the breast. Expert Rev Anticancer Ther. 2012
Feb;12(2):215-21. PubMed PMID: 22316369.
Khodjet-el-Khil H, Fadhlaoui-Zid K, Gusmão L, Alves C, Benammar-Elgaaied A, Amorim A. Allele frequencies for 15
autosomal STR markers in the Libyan population. Ann Hum Biol. 2012 Jan;39(1):80-3. Epub 2011 Nov 1.
Lebreiro A, Martins E, Almeida J, Pimenta S, Bernardes JM, Machado JC, Abreu-Lima C. Value of Molecular Diagnosis in a
Family With Marfan Syndrome and an Atypical Vascular Phenotype. Rev Esp Cardiol 64:151-154, 2011.
Lebreiro A, Martins E, Machado JC, Abreu-Lima C. Diagnostic challenges of Marfan syndrome in an XYY young man. Cardiol
Young 2011 (in press).
Martins D, Sousa B, Lopes N., Gomes M, Veronese L, Albergaria A, Paredes J, Schmitt F, Molecular phenotypes of
matched in situ and invasive components of breast carcinomas: Human Pathology 42: 1438-1446, 2011.
Mendizabal I, Valente C, Gusmão A, Alves C, Gomes V, Goios A, Parson W, Calafell F, Alvarez L, Amorim A, Gusmão L,
Comas D, Prata MJ (2011) Reconstructing the Indian origin and dispersal of the European Roma: a maternal genetic
perspective. PLoS One 6(1):e15988.
Morling N, Schneider PM, Mayr W, Gusmao L, Prinz M (2011) Authentication of forensic DNA samples. Forensic Sci Int
Genet. 5(3):249-250.
Pinheiro C, Sousa B, Albergaria A, Paredes J, Dufloth R, Vieira D, Schmitt F, Baltazar F. GLUT1 and CAIX expression profiles
in breast cancer correlate with adverse prognostic factors and MCT1 overexpression. Histol Histopathol 26: 1279-1286,
2011.
Prieto L, Zimmermann B, Goios A, Rodriguez-Monge A, Paneto GG, Alves C, Alonso A, Fridman C, Cardoso S, Lima G, Anjos
MJ, Whittle MR, Montesino M, Cicarelli RM, Rocha AM, Albarrán C, de Pancorbo MM, Pinheiro MF, Carvalho M, Sumita
DR, Parson W (2011) The GHEP-EMPOP collaboration on mtDNA population data--A new resource for forensic casework.
Forensic Sci Int Genet. 5(2):146-51.
Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle Teijeiro J, Milanezi F, Schmitt F, Paredes J. Breast cancer stem
cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol
10.1136/jcp.2011.
63
15. Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F, Paredes J. Breast cancer
stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol. 2011
Nov;64(11):937-46. Epub 2011 Jun 16. PubMed PMID: 21680574.
16. Santos LF, Pereira T, Rodrigues B, Correia E, Moreira D, Nunes L, Costa A, Elvas L, Machado JC, Castedo S, Henriques C,
Matos A, Oliveira Santos. Critérios de diagnóstico da Síndrome de Brugada. Podemos melhorar? Rev Port Cardiol 2011 (in
press).
17. Santos LF, Rodrigues B, Moreira D, Correia E, Nunes L, Costa A, Elvas L, Pereira T, Machado JC, Castedo S, Henriques C,
Matos A, Oliveira Santos. Criteria to predict carriers of a novel SCN5A mutation in a large Portuguese family affected by
the Brugada syndrome. Europace (in press).
18. Schmitt F, Barroca H. Role of Ancillary studies in fine-needle aspiration from selected tumors. Cancer Cytopathology DOI
10.1002/cncy.20197, 2011.
19. Schmitt F, Cochand-Priollet B, Toetsch M, Davidson B, Bondi A, Vielh P. Immunocytochemistry in Europe: results of the
European Federation of Cytology Societies (EFCS) inquiry. Cytopathology 22: 238-242, 2011.
20. Schmitt FC. Molecular cytopathology and flow cytometry: pre-analytical procedures matter. Cytopathology 22: 355-357,
2011.
BOOK CHAPTERS/CONFERENCE PROCEEDINGS
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7.
Gomes C, Magalhães M, Amorim A, Alves C, Pinto N, Gusmão L (2011) How useful is your X in discerning pedigrees?
Forensic Science International: Genetics Supplement Series 3:e161-e162.
Magalhães M, Pinto N, Gomes C, Pereira R, Amorim A, Alves C, Gusmão L (2011) When the alleged father is a close
relative of the real father: The utility of insertion/deletion polymorphisms. Forensic Science International: Genetics
Supplement Series 3:e9-e10.
Ferreira Santos L, Pereira T, Rodrigues B, Correia E, Moreira D, Vidinha J, Nunes L, Costa S, Machado JC, Castedo S,
Henriques C, Matos A, Oliveira Santos. Is there a Signal-Averaged ECG phenotype in patients with Brugada Syndrome?
CardioRhythym, HongKong, China, 2011.
Pereira T, Ferreira Santos L, Rodrigues B, Correia E, Moreira D, Nunes L, Costa S, Machado JC, Castedo S, Oliveira Santos.
Reproducibility of the signal-averaged ECG in a family screened for Brugada syndrome. CardioRhythym, HongKong, China,
2011.
Cirnes L, Fernandes R, Pina MJ, Ribeiro C, Sousa S, Machado JC. Caracterização das mutações do gene KRAS em doentes
com carcinoma do cólon e recto metastático e do gene EGFR em carcinoma do pulmão metastático. Encontros da
primavera em Oncologia. Évora, Portugal, Março de 2011.
Costa JL, Sousa S, Fernandes R, Cirnes L, Machado JC. Non-optival massive parallel sequencing of BRCA1 and BRCA2 genes:
towards the diagnostic setting. 15ª Reunião Anual sa SPGH. Lisboa, Portugal, Novembro de 2011.
Dequeker E, Bellon E, Ligtenberg M, de Hertogh G, de Stricker K, Edsjö A, Laurent-Puig P, Machado JC, Rouleau E, van
Krieken H. European external quality assessment for the improvement of KRAS testing. 23rd European Congress of
Pathology. Helsinki, Finland, August, 2011.
INVITED TALKS
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-
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António Amorim. A prova genética em investigação de identidade e parentesco. Semana da Ciência e Tecnologia, ES
Aurélia de Sousa. Porto, Portugal. 23/11/2011.
António Amorim. Genética Forense. V Jornadas de Análises Clínicas e de Saúde Pública , Escola Superior de Saúde,
Instituto Politécnico de Bragança. Bragança, Portugal. 21/05/2011.
António Amorim. Genética populacional - aplicações nas perspectivas forenses e de biodiversidade. Palestras PPGEE –
UERJ. Rio de Janeiro, Brazil. 27/06/2011.
António Amorim. Produção e interpretação da prova genética. Workshop Prova genética em investigação de identidade e
parentesco: as dimensões pericial, judicial e societal. Porto, Portugal. 25/11/2011.
Cíntia Alves. 2011 Collaborative Exercise Results – Non-human sample M7. XVI Jornadas GHEP-ISFG. Vienna, Austria,
29/08/2011.
Fernando Schmitt. "Soft tissues FNA: Practical issues", Theoretical-practical course on non-gynecological cytology,
realizado em Barcelona, Espanha, no período de 19 a 21 de Jáneiro de 2011.
Fernando Schmitt. "Cytology and Lung Cancer: Role in Diagnosis and Therapeutic Guidance", Theoretical-practical course
on non-gynecological cytology, realizado em Barcelona, Espanha, no período de 19 a 21 de Jáneiro de 2011.
Fernando Schmitt. "Breast Cytology: Can This Simple Diagnostic Test Provide Sophisticated Answers?", Theoreticalpractical course on non-gynecological cytology, realizado em Barcelona, Espanha, no período de 19 a 21 de Jáneiro de
2011.
Fernando Schmitt. "Current trends in Breast Cancer” A joint meeting between APTAP and UK NEQAS to celebrate 25
years, realizado em Carcavelos, Portugal, em 05 de Fevereiro de 2011.
Fernando Schmitt. "Breast cancer-therapeutic targets and molecular classification”, International CME in Pathology –
Histopathology and Cytopathology Goa Medical College, realizado em Goa, Índia, no período de 10 a 12 de Fevereiro de
2011.
Fernando Schmitt. "Molecular Cytopathology”, International CME in Pathology – Histopathology and Cytopathology Goa
Medical College, realizado em Goa, Índia, no período de 10 a 12 de Fevereiro de 2011.
Fernando Schmitt. "Lung Cytology”, International CME in Pathology – Histopathology and Cytopathology Goa Medical
College, realizado em Goa, Índia, no período de 10 a 12 de Fevereiro de 2011.
64
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Fernando Schmitt. “The use of immunocytochemistry in everyday practice” 6th CE Regional Meeting – Cytopathology,
realizado em Balatonfured, Hungria no periodo de 07 a 09 de Abril de 2011.
Fernando Schmitt. “One size does not fit all! Finding therapeutic targets for subgroups of breast cancers” XX Porto Cancer
Meeting “Drug Resistance in Cancer: from biology to molecular target and drugs”, realizado no Porto, Portugal no
periodo de 28 a 29 de Abril de 2011.
Fernando Schmitt. “Vias de sinalização celular e novos tratamentos em Oncologia” na Sessão Inovação em Oncologia,
realizada em Lisboa, Portugal no dia 10 de Maio de 2011.
Fernando Schmitt. “Tumoral angiogenesis” no Simpósio GIST – Challenging the future, realizada na Cúria, Portugal no dia
14 de Maio de 2011.
Fernando Schmitt. “Seminar Speaker for Hong Kong Society of Cytology in the Year 2011”, realizado em Hong Kong, nos
dias 19 e 20 de Maio de 2011.
Fernando Schmitt. “From the cells to the molecules. An overview of molecular applications on cytology” The 7th Asia
Pacific IAP Congress, realizado em Taipei , Taiwan no periodo de 20 a 24 de Maio de 2011.
Fernando Schmitt. “Cáncer de Mama: Grado de diferenciación en índice proliferativo o firma génica?” na XVII Reunión
Nacional de la Sección de Patología Mamaria, realizado em Vigo, Espanha, no período de 09 a 10 de Junho de 2011.
Fernando Schmitt. “Citopatologia Molecular” no VII Congrés Català de Citopatologia, realizado em St. Fruitós de Bages,
Barcelona – Espanha, no período de 10 e 11 de Junho de 2011.
Fernando Schmitt. “National investigation – preliminary results from the Re-Testing Study”, no Personalized Healthcare in
Oncology, realizado em Lisboa, Portugal, no período de 16 a 17 de Junho de 2011.
Fernando Schmitt. “Nuevos horizontes en la Baaf de Cáncer Mama”, no XVI Congresso
Latinoamericano, realizado em Lima, Peru, no período de 21 a 23 de Junho de 2011.
Fernando Schmitt. “Pruebas Moleculares en Citologia”, no XVI Congresso Latinoamericano, realizado em Lima, Peru, no
período de 21 a 23 de Junho de 2011.
Fernando Schmitt. “Signaling pathways as a target for cancer treatment” no Advanced Drug Delivery Solutions for Cancer
Therapy, realizado no Anfiteatro da Faculdade de Farmácia da Universidade do Porto, no dia 27 de Junho de 2011.
Fernando Schmitt. “Resident’s Puzzle- Interactive Session ” no 36th European Congress of Cytology, realizado em Istanbul,
Turquia, no periodo de 22 a 25 de Setembro de 2011.
Fernando Schmitt. “P-Caderina no Cancro da Mama: o percurso de uma investigação” nas XIII Jornadas de Senologia,
realizado em Viseu, Portugal no dia 08 de Outubro de 2011.
Fernando Schmitt. “A Importância de um Programa de Controlo de Qualidade no laboratório de AP – Resultados Finais do
Estudo RETESTE” nas XIII Jornadas de Senologia, realizado em Viseu no dia 08 de Outubro de 2011.
Fernando Schmitt. “Câncer de Mama: Grau histológico e indice proliferativo ou assinatura gênica?” no XVI Congresso
Brasileiro de Mastologia, realizado em Goiânia, Brasil, no período de 19 a 22 de Outubro de 2011.
Fernando Schmitt. “Carcinoma mamário triplo negativo”” no Hospital Araújo Jorge da Associação de Combate ao Câncer
em Goiás”, realizado em Goiânia, Brasil, no dia 21 de Outubro de 2011.
Fernando Schmitt. “Identification of genomic mutations in thyroid FNBA”, no 8th Multidisciplinary Course on Thyroid
Pathology and Cytology, realizado em Roma, Itália, no período de 18 a 19 de Novembro de 2011.
Fernando Schmitt. “Molecular Diagnosis in Breast Cytology”, no Winter Meeting of Belgian Society of Clinical Cytology,
realizado em Bruxelas, Bélgica, no dia 09 de Dezembro de 2011.
José Carlos Machado. Biomarcadores no CCRm. 5º Simpósio Nacional EGFR. Cascais, Portugal, Fevereiro de 2011.
José Carlos Machado. Da molécula ao medicamento. Simpósio APIFARMA. Porto, Portugal, Junho de 2011.
José Carlos Machado. Instabilidade de microssatélites. Qual a sua importância? 7º Simpósio Nacional e Cancro Digestivo.
Albufeira, Portugal, Outubro de 2011.
José Carlos Machado. Marcadores moleculares no cancro do pulmão: O ponto de vista laboratorial. Reunião da Comissão
de Pneumologia Oncológica. Monte Real, Portugal, Novembro de 2011.
José Carlos Machado. Diagnóstico Genético en Cardiologia. Perspectiva Clínica. I Jornada de Diagnóstico Genético en
Cardiologia. Madrid, Espanha, Dezembro de 2011.
Leonor Gusmão. Características do cromossoma Y: polimorfismos e aplicações em genética forense (2h). Curso de
Mestrado em Medicina Legal e Ciências Forenses (5ªEdição) da Faculdade de Medicina de Lisboa. Lisboa, Portugal, 8 de
Janeiro de 2011.
Leonor Gusmão. Marcadores do cromossoma X em investigação de parentesco (2h). Curso de Mestrado em Medicina
Legal e Ciências Forenses (5ªEdição) da Faculdade de Medicina de Lisboa. Lisboa, Portugal, 8 de Janeiro de 2011.
Leonor Gusmão. N. Pinto, L. Gusmão, W. Parson. Interpretation of mtDNA and Sex chromosome Results in the Forensic
Field. Workshop. Universidad de Alcalá, Alcalá de Henares (Madrid), Spain. 09/2011.
COLLABORATION IN MASTER PROGRAMS
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Forensic Genetics Masters Course, Faculty of Sciences of University of Porto, Portugal.
Projects
Collaboration in FCT project “Mothers and fathers after the "biological truth"? Gender, inequalities and parental roles in
the cases of investigation of paternity”, PIHM/PI/0020/2008.
Collaboration in ADI project “Anti EGFR Effective”.
Collaboration in GEDDI project “Identification of genetic markers for prediction of the clinical course and development of
complications in Portuguese Crohn’s Disease patients”.
65
INTERNAL SERVICES
66
SEQUENCING SERVICE
OVERVIEW
The sequencing service continued maintaining and handling the automated sequencers present in IPATIMUP facilities and also
organizing the samples delivered on each day and distributing them through the appropriate instrument. It is also responsible for the
acquisition and distribution (at an internal level) of some wide use consumables. Whenever needed, the sequencing service also
gives support in sequencing/fragment analysis softwares.
HIGHLIGHTS
Utilization of the instruments 3130xl/3130 increased 9% in 2011. The number of samples processed by the Sequencing Service
increased from 75.278 in 2010 to 83.138 in 2011, which corresponds to a utilization percentage of 74% in 2010 to 83% in 2011.
Samples processed
9.000
8.000
7.000
6.000
5.000
4.000
3.000
2.000
1.000
0
January
February
March
April
May
June
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July
August
September
October
November December
PROTEOMICS SERVICE
OVERVIEW
IPATIMUP proteomics unit provides investigators access to the analysis of protein samples from solutions, bands or protein spots
from 1D or 2D SDS gels.
Our mass spectrometer is optimized for the use in the following proteomic studies:

Mass Analysis of Intact Proteins, Peptides and Metabolites by mass spectrometry.

Protein identification by Peptide Mass Fingerprint -PMF (MALDI-TOF).

Protein identification by PMF following peptide sequencing/fragmentation (MALDI-TOF/TOF, PMF+MS/MS).
HIGHLIGHTS
In 2011 were analyzed, by the IPATIMUP Proteomics Unit, a total of 354 samples, corresponding to 44 tasks from the different
institutions / research groups: IPATIMUP (Cancer Biology, Cancer Genetics, Carcinogenesis, Population Genetics, Proteolysis in
diseases), IBMC (Ageing and Stress, Bioactive Natural Products, Biomolecular Structure, Cellular and Applied Microbiology, Molecular
Biology of Nitrogen Assimilation , Molecular Genetics, Molecular Microbiology, Molecular Neurobiology, Nerve Regeneration), INEB
(NEWTherapies Group), Porto University (CIIMAR and ICBAS), Minho University, ISA and FMV from Technical University of Lisbon and
Coimbra University.
The performed analysis corresponded to:

Molecular weight determination – 97 samples.

Protein identification and characterization by Peptide Mass FingerPrint (PMF) – 127 samples.

Protein identification and characterization by Peptide Mass FingerPrint (PMF) and MS/MS de novo peptide sequencing –
130 samples.
In 2011, the Proteomic Unit of IPATIMUP participated in national and european projects leading to the publication of various articles
in international scientific journals. Two new FCT projects were funded, in the FCT call that ended in 2011, involving the material and
human resources of the IPATIMUP Proteomics Unit. Together with CIIMAR, the IPATIMUP Proteomics Unit has organized a
Proteomics Workshop open to the entire scientific community.
The Proteomic Unit of IPATIMUP has submitted a proposal in 2011 to be a full member of the RNEM (Rede Nacional de
Espectrometria de Massa).
PROJECT PARTICIPATION

FCT funded project, "Early detection of cancer using serum biomarkers based on aberrant post-translational modifications
of O-glycoproteins", Ref. PIC/IC/82716/2007; PI: Celso Reis.

European Project "Discovery of novel cancer serum biomarkers based on aberrant post translational modifications of Oglycoproteins (O-PTM Biomarkers) and their application to early detection of cancer". Sponsor: EU (FP7), Grant no.
201381; PI: Leonor David. Coordinator: Prof. Joyce Taylor-Papadimitriou (UK).
TRAINING / FORMATION PROGRAMS

PhD Program for MD from Gulbenkian / Champalimaud foundation

GABBA graduated program from University of Porto

Organization of the Proteomics Workshop together with CIIMAR
RELEVANT PUBLICATIONS

Soares S, Vitorino R, Osório H, Fernandes A, Vena^ncio A, Mateus N, Amado F, de Freitas V (2011). Reactivity of human
salivary proteins families toward food polyphenols. J Agric Food Chem, 25, 5535-5547.

Barbosa AD, Osório H, Sims KJ, Almeida T, Alves M, Bielawski J, Amorim MA, Moradas-Ferreira P, Hannun YA, Costa V
(2011). Role for Sit4p-dependent mitochondrial dysfunction in mediating the shortened chronological lifespan and
oxidative stress sensitivity of Isc1p-deficient cells. Mol Microbiol, 81, 515-527.

Reis CA, Campos D, Osório H, Santos LL (2011). Glycopeptide microarray for autoantibody detection in cancer. Expert Rev
Proteomics, 8, 435-437.

Beites T, Pires SD, Santos CL, Osório H, Moradas-Ferreira P, Mendes MV (2011). Crosstalk between ROS Homeostasis and
Secondary Metabolism in S. natalensis ATCC 27448: Modulation of Pimaricin Production by Intracellular ROS. PloS one 6:
e27472, 2011.
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COMMUNICATIONS IN SCIENTIFIC MEETINGS

I3S Scientific Retreat 2011, Póvoa de Varzim: IPATIMUP Proteomics Unit – Research activities and services to scientific
community. Hugo Osório, Celso A. Reis

XXI International Symposium on Glycoconjugates, Vienna, Austria, 2011: Glycoconjugate Journal 28(5): 264.

Glycan biomarkers in gastric lesions: tissue and serum characterization. Gomes C, Silva L, Pinto-de-Sousa J, Santos-Sousa
H, Schwientek T, David L, Reis C, Osorio H.
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ANIMAL MODEL SERVICE
OVERVIEW
IPATIMUP’s Animal House is working as a service since 2009 and concluded its certification process as a competent facility in the use
of small rodents for research purposes by “Direcção Geral de Veterinária”, the National Regulator Entity (DGV), in November 2010.
Personnel working directly in the Animal House include a Veterinarian doctor (Director), a Research technician (Responsible
technician/Coordinator) and 2 Animal Handlers. All personnel are certified by DGV under National and European Laws. We maintain
at the facility two types of animals distinguished according to its microbiological status – immunodeficient strains and conventional
strains - both of them having different physical conditions in terms of air pressure of the rooms and also access permits. Animal
maintenance areas are kept under controlled conditions of light and humidity and are divided in two separated areas. One of these
areas is maintained in “SPF-like” conditions to allow the maintenance, reproduction and also the investigation process using an
immunosuppressed mouse strain (nude mouse model), not commercially available (strain: N: NIH(s) II-nu/nu), under very limiting
conditions of maintenance and care. These mice with combined immunodeficiency (Azar HA et al, 1980) support the growth of
human and animal tumor xenografts allowing the researchers to validate their in vitro models of tumorigenesis, invasion,
metastization and/or response to certain drugs. The other “main” area, divided in 3 separated rooms, is for maintenance and
expansion of conventional mice strains, transgenic and/or knockout, received by IPATIMUP’s researchers. These mice have overexpression or no-expression of certain cancer-associated genes under study. At this moment the Animal House is at its maximum
capacity and the acquisition of new mice models is not possible. At our institution all in vivo research, is regulated by the European
and National Law that standardize the use of animals in research. The 3Rs (that is the replacement, refinement and reduction of the
use of animals in research) are implicit in the Directive 2010/63/EU of the European Parliament and of the Council of 22nd
September 2010 on the protection of animals used for scientific purposes. Any researcher planning to use animals in their project
research has to first demonstrate why there is no alternative method, justify the number of animals plan to be used and prove that
any suffering or distress will be kept to a minimum. All the research protocols are made under direct supervision.
HIGHLIGHTS
Main areas:
1. Tumor biology research – tumorigenesis, invasion, metastization and response to stimuli NIH(s) II-nu/nu mice are breeded in our
Facility. Reproduction level is maintained in a reasonable level in order to maintain (1) an outbred colony of genetically-variable
composition mice, (2) allow the periodic substitution of active reproductive couples and (3) improve the reproduction level when
there is the need to perform experiments. During the year 2011, and taking into account only assays starting in the year under
analysis, we performed 9 in vivo assays. In terms of type of experiment, 4 were metastization assays, 4 tumorigenesis assays and 1
was tumorigenesis associated to response to therapy. In all of these cases, all the procedures, invasive (examples: inoculation of
tumor cells, surgical procedures) or not (examples: monitorization of animal health status, anthropometric parameters registry) ,
were done under the directives that regulate the use and care of laboratory animals and were performed by the Responsible
Technician or its Director, always aided by a well trained Animal Handler. During this year, we also concluded 4 other assays that
started in 2010, in which one was performed in collaboration with IPO- Francisco Gentil, Porto. In particular, this one made with IPOPorto, was a xenograft research model that lasted, in time, for more than one year, ending in 2012. Number of animals, days of
experimentations and procedures will be presented in the point “Activity statistics”.
2. Conventional strains - maintenance and expansion of transgenic and/or knockout mice. Until July 2011, IPATIMUP Animal House
maintained 4 strains of knockout (KO) mice (C57BL/6 background) and one strain wild-type-like C57BL/6 mice. These mice were
obtained from Carcinogenesis research group (namely Celso Reis, PI) in 2006. During 2011 no experimentation was performed using
these models (in contrast with previous years) so that maintenance, reproduction and colony management, tasks performed by
Animal House personnel, were kept in a reasonable level (4 to 5 active reproductive couples per strain) to assure the existence of
viable mice, except for one KO strain that had to be backcrossed in order to maintain safely the colony. For this reason, the number
of couples and mice in this particular stain (SU strain) is above the reasonable level during all year. In July the Facility received 2 new
mouse models (2 males and 2 females, each of one baring a certain genotype) from another researcher (Raquel Almeida, from
Carcinogenesis group). These mice colonies are being expanded so that the real number of mice in need is not yet known. A similar
procedure is being done with another 2 mouse models (2 males and 2 females) obtained from Cancer Biology group that arrived in
December 2011. All the manipulations done in the animals are performed by the personnel from the Facility accompanied by the
certified researchers. Number of animals and couples per month will be presented in the point “Activity statistics”.
70
ACTIVITY STATISTICS
Animals per Day per Month
400
300
200
100
0
Jan
Fev
Mar-Mai
Jun
Jul
Ago
Set
Out
Nov
Dez
QUALITY CONTROL
In 2011 the 2 Animal Handlers of the Animal House have participated in the Course “Science in Laboratory Animals – Class A0”, in
accordance with FELASA considerations for the use and care of laboratory animals (Directive 2010/63/EU of the European Parliament
and of the Council of 22nd September 2010) and to obtain certification by DGV according to “ponto iii), da alínea e), do n.º3 da
Portarian.º 1005/92” under National Law.
OTHER ACTIVITIES
During 4 weeks in 2011, the facility rented a room, as a service, to the Faculty of Medical Dentistry– Porto so that an experiment with
16 rats distributed by 8 cages could be performed. The same was made between March and May with an experiment carried out by
the FMUP (Medical Faculty of the University of Porto).
Animal Model Facility also gave support to the researchers in the licensing process by the National Regulator (DGV) of all the
performed experimentations. Is important to refer that during the all year the researchers and the Facility only had feedback from
DGV about the first two.
71
CELL LINES BANK
OVERVIEW
IPATIMUP’s Cell Line Bank (BLC) main goals are maintenance of stocks of parental cells characterized for their genetic profile (genetic
identity) and microbiological status, in particular infection by bacteria of the genus Mycoplasma. BLC is composed by a collection of
parental cell lines, mostly tumors of various histological topographies, provided by the research groups of IPATIMUP and
representing an unquestionable heritage of the Institute. The vast majority of the BLC cell lines were commercially obtained.
However, others were established at the Institute and were provided by external institutions under scientific collaboration.
HIGHLIGHTS
During the year 2011 IPATIMUP’s BLC continued the permanent task of maintaining stocks of cell lines already characterized within
the quality parameters as well as receiving and starting new cultures provided by internal research groups. This is a continuous task
and new cell lines are always arriving to fulfill researchers and research needs. It was also during 2011 that the internal services
provided by IPATIMUP’s Cell Line Bank were established. These include (1) provision of parental cell lines genotypically characterized
and tested for contaminants (specifically bacteria of the genus Mycoplasma), provided in frozen aliquots or in culture and (2)
Mycoplasma testing to cell samples donated by internal research groups and (3) support in acquisition of new commercially available
cell lines. BLC’s personnel also gives support in any case of cell culture problems, recommendations for the use of consumables (for
example, FBS control and acquisition) and any other question considered relevant for the improvement of in vitro quality
performance. Another task that is being taken is the updating at IPATIMUP’s website of the considered relevant information about
each particular cell line, available internally to all researchers. For this purpose an “information management system” had been
developed in collaboration with Informatics Department.
ACTIVITY STATISTICS
0
50
100
150
200
Lymphoblastic cells
Gastic Ca.
colorectal Ca.
Uveal melanoma
Thyroid Ca.
Renal Ca.
Breast Ca.
Leukemia
lung Ca.
Glyoblastoma
Endothelial cells
Bladder carcinoma
Cervix Ca.
Frozen Vials
CL Maintained
QUALITY CONTROL
We perform a internal control for microbiological status, specifically in the case of Mycoplasma infection, using a commercial kit
based on high specific PCR techniques. All the controls, positive, negative and internal (to test the performance of the reaction itself)
are included. We also microscopically check all the BLC cell lines in culture and perform bacterial and fungal examinations when
there is the suspection of other possible infections. The genetic identification of our cell lines is made by IPATIMUP's Diagnostic
Service, which is a certified service.
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TECHNICAL BODY
OVERVIEW
The Technical Body is responsible for the management of the IPATIMUP’s common research resources, crossing the different areas
and research groups:

Keeping the equipments and common rooms (like cell culture rooms) in a good maintenance status;

Planning and monitoring the use of those equipments by the different researchers;

Establishing, together with the Board of Directors, procedures and good work practices

Proposing to the Board of Directors technical solutions to problems related with the laboratories management;

Running the equipments logging system;

Training new users.
The Technical Body has the direct operational responsibility of the Sequencing, Fast Real Time PCR, Qiaxcel and Cell Line Bank (BLC)
HIGHLIGHTS
GENERAL ACTIVITIES
•
Coordination of the Technical Body Services. The technical body technicians ensure the continuous functioning of all
technical body associated services and equipments;
•
Coordination of the Scientific Equipment Acquisition Processes
•
Management of the Calibration Service for micropipettes
•
Management and maintenance of the Equipment Inventory (in the GPLI System)
•
Participation in the Risk Management Commission
•
Licensing process of the Radioimmunoassay lab.
•
Management of the Maintenance Contracts for scientific equipments
•
Management Dioxide Carbon and Liquid Nitrogen supply
LAB RULES and USER LOGS
•
Implementation of rules for the access and use of cell cultures rooms;
•
Implementation of Rules for the access and use of liquid Nitrogen
•
Conclusion of the Radiologic Plan for the IPATIMUP Radioimmunoassay laboratory;
•
Implementation of rules for the access and use of -80oC Deep Freezers
•
Implementation of rules for the access and use of Advanced Microscopy Room
•
Establishment in collaboration with the Risk Management Commission of a document on the Groups 3 and 4 Residues:
From Production to Disposal;
MAINTENANCE ACTIVITIES
•
Implementation of new rules residues for the Group III and IV residues discard ;
•
Monthly maintenace of the -80oC freezers;
•
Weekly monitoring/maintenace of liquid nitrogen levels in the containers LN2 and of their content;
•
Equipment/Rooms Logbooks maintenance;
•
Sequencing Room: Maintenance/calibration of the Sequencers and Real Time PCR devices; Maintenance of Flow
Cytometer.
•
Advanced Microscopy Room – Schedulling and access rules
•
Centrifuge and Incubators Room
•
Cell Culture Rooms: Procedures for the cleaning of equipments were established (Cell Cult. Room 1 and 2); New distinct
labcoats were provided to be used exclusively in these rooms;
•
Biosafety Level 2 Room: Implementation of the use of distinct beige/yellow lab coats for the bacteria/virus lab.
•
Warehouse – space usage optimization.
•
Implementation of a plan for cleaning the floors of laboratories and commom areas
TRAINING ACTIVITIES
•
FlowJo Software Training, 25th July by Patricia Pereira from Celeza GmbH;
•
Time Lapse Microscope Training: 13,14 and 15th June by Jordi Recasens from IZASA (1st action); 21 and 28th November
by Patricia Castro from IPATIMUP (2nd action);
•
Autoclave Steri21 Training, 31th August by Bruno Coelho and Joaquim Costa from AJCosta (Irmãos) Lda.;
•
SNAP i.d. Protein Detection System, 2nd July by Bruno Moreira and Henrique Berlanas from Merck Millipore;
•
Real Time PCR Basic Fundamentals and Results Analysis, 15th November 2011 by Maria de Jesus Garcia from
Lifetechnologies;
OTHER ACTIVITIES
•
Creation of the Cell Line Bank as an internal service.
•
Coordination of the installation of the new research groups: Cancer Drug Resistance and Proteolysis and Diseases.
73
CORE SERVICES
74
INFORMATICS
OVERVIEW
The main goal of this service it’s to give access to the Institute Researchers all necessary tools available to register, promote and
publish their work.
Our Unit it’s divided in 2 areas, the Networking and the Information System. The networking staff is responsible for the maintenance
and configuration of all informatics infrastructure and gives helpdesk support for all informatics equipment. In other hand the
Information System staff is responsible for the creation and maintenance of all web applications mainly created in the Outsystems
Platform.
HIGHLIGHTS
Homebanking [Development].
This module gives the possibility to generate a reference ATM, and register your payment. Can be used in payment of registrations of
events, and payments of other funcionalities.
WhoIsIn Module [Development].
The main purpose of this module is to control the access to the building. In the initial phase of the application was available outside
of normal working hours, weekends and holidays.
BPM Utils [Development].
This Module is a complement to the existing Business Process Management of the Outsystems. The main purpose is to have a set of
tools which allows creating Workflows in an easier, automatic and faster way. It allows to specify the available actions associated to a
Human Activity, send emails automatically where the user can decide without the need of authentication. Is also possible to justify a
decision and to attach files on it. It was developed the BPM Groups where is possible to associate a Human Activity to a sub-group of
users. Because Human Activities could be opened for a long time because users don't close them, it was created Timeouts that
inform users periodically or even decide in case users don't. It was also developed an Application Program Interface (API) that
handles permissions, validations, status...
Absence Notification Module [Development].
Allows users to notify their absences. Is also possible to schedule, cancel or change vacations. It was on this module where it was
created the first workflow. An absence has to be approved by the Group Leader and then validated by Human Resources.
Personal Calendar Module [Development].
Is a calendar where the user can visualize absences (missions, vacations, licenses, health) per year. It has also the group calendar,
where in the same page user can see per month the absences of his colleagues on an organization unit.
Activity Report Module [Development].
Development of interfaces where users can submit all activities executed during one year on an organization unit and see the
preview of the activity report. It has also a Workflow where all the activities need to be approved by the group leader.
Paper Registration Module [Development].
This module allows users to register their papers on Ipatimup Data Base.
Paper Reivindication Module [Development].
Interface and workflow where users can reinvidicate the authorship of a paper (first or senior).
Editorial Board Registration [Development].
The main purpose is to inform the institution that the person belongs to the editorial board of a specific magazine.
Person Admission Module [Development].
The goal of this module is to admit internships, PhD students, Post-Docs and insert personal data into the data base. For that, it was
developed four Workflows (Identification, Internship, PhD Student and Post-Doc).
Utils Ipatimup Extension Module [Development].
This module provides actions which complement the ones provided by Outsystems, actions which call C# functions and actions which
implement utilities.
Requisitions by Service List [Development].
New functionality in the Requisitions module, allows make requisitions of internal services from a predefined list. Thus allowing
better management of accounts and related items.
Scheduler Module [Development].
The main objective is to reduce Software Units and keep better management of existing timers in all Modules in only one place. The
main features of this module are create and schedule actions, log of the actions executed, control any errors and if necessary disable
automatically the action with errors.
InfoSaude [Development].
The goal was to create a Slideshow related document "O Cancro" and "Perguntas Frequentes". In each of the slides have a menu for
easy access to such topics and chance to ask IPATIMUP a question related to the theme.
Site Contacts[Development].
Development of Internal Contacts of IPATIMUP (extension searching fields)
75
Site-Submission of Abstracts [Development].
Allows submitt abstracts in the event regsitrations.
Site - Project and Paper Charts [Development].
New functionality on the site, with graphics showing statistics about research projects and papers of IPATIMUP.
Document Generator [Development].
Development of a module that allows you to create documents from contributions from a previously defined group of people, these
contributions will then be accepted or changed, thus creating the final document. The document structure can be defined in advance
in order to limit the amount or type of information to be introduced.
Networking:
•
During the last year we did several firmware upgrades to the Barracuda SPAM system. We have some server’s discs
broken and they were replaced by new ones, during this process none of the informatics services stopped. At July we
finished the McAfee anti-virus migration to 8.8, but at the end of September we were informed by the Universidade
Digital, Oporto University software service, that they will not support no more the McAfee antivirus system, and instead
they will support the Symantec Endpoint Protection system. Facing this scenario, the migration of the antivirus system
was planned, and at the beginning of November it was started. This operation, replacing one software by another, took
about one month to accomplish and one of the main goals was to avoid the disrupt of the services. It was necessary to
change the computers layout on the library, to give room to the people with personal laptops; to put some PC’s with
specific software available to all and to transform the smaller room in classroom when needed. These changes took place
at July.
•
The telephone network is managed by our department, and some operations like create new telephones extensions,
unlock telephones for external calling and resolution of other minor problems are performed by us.
•
All software maintenance is performed by our department, like upgrading versions or changing licenses. When asked by
the users, we install specific software on the computers of the Institution or in the personal laptops, if there is a valid
license to perform this task. This year we started updating operative system from Windows XP to Windows 7. All the
computers in the library are now updated, but there are still computers that need to be updated and we are still working
on it. Devices that make image acquisition like Gel Doc or cameras that are attached to microscopes, need to be
connected to computers or directly to the network and we give technical assistance to the equipment's responsible.
•
To deploy quickly a PC we had a software called Tivoli Provisioning Manager that manage all the IPATIMUP's PC images,
and this software where very useful to deploy Windows XP workstations. But when we started to migrate some
workstations to Windows 7, we realized that we couldn't make images from Windows 7 with the Tivoli, and so, we started
looking for an alternative. After some research we discovered one free images server called Clonezilla, that supported
Windows XP and Windows 7 images, and implemented it on our network.
ACTIVITY STATISTICS - HELPDESK
Type
Informatics > Computer
Informatics > Computer > Hardware
Informatics > Computer > Software
Informatics > Internet
Informatics > Printer
Informatics > Video Projector
Helpdesk Team [Networking]
Number of tickets
223
29
123
16
207
1
599
Number of resolved tickets
226
30
124
14
206
1
598
76
Average resolution delay
7 Day(s) 17 Hour(s) 7 Min(s)
17 Hour(s) 55 Min(s)
SECRETARY GENERAL
OVERVIEW
The General Secretary carries out the general administrative tasks of IPATIMUP and the management of treasury and research
projects.
It comprises the accounting and all operations required for management of human resources and events. The accounting official
technician and the legal advisor are outsourced.
It plays an important role on projects management, assuring all the tasks of financial reporting and related counselling to the
principal investigators.
HIGHLIGHTS
General highlights
Several innovative workflows were implemented during 2011, along with the development of tools provided by the information
informatics system, as the admission of personnel and the absence registration.
After the deliberation of the Board of Directors to create a plan of cost containment, it was defined and has been monthly updated a
controlling table for infrastructural expenditure. Within this plan, new internal rules for catering and request of stationary were
implemented.
The information system
Using the management software developed inhouse, it was created a database to support the General Secretary in the execution
and control of the research projects, in the equipment maintenance and in the Human Resources organization. The information
system has been significantly increasing the availability and accessibility to information, and the response capacity of the
administrative services, allowing also the transparency in the accounts provision.
Treasury
The payment to suppliers is carried out weekly and all invoices are paid in due time (generally 30 days after the invoice emission).
The processing of salaries and fellowships is carried out on a monthly basis, after approval by the Coordinating Council. The
reimbursement of expenses in cash has been reduced.
Expenses Containment Plan
The new expenses containment plan implemented at the end of the year has obliged to the internal restructuring of some
administrative services, as the mailing of correspondence and the acquisition of office material . These costs were significantly
reduced.
Accounting and project finantial reporting
The accounting is made in accordance with the SNC – Standard Accounting System, using a certified software (SAGE). All assets are
labelled.
In 2011, we have started to scan all possible paper documents, with direct link to the accounting software.This process has improved
the administrative and financial management of research projects, since it has significantly reduced the number of copies, allowing
an easier submission of payment requests.It was developed an electronic report on the accounting software, with the same format
of the payment request for FCT.
The platform of the Portuguese Foundation for Science and Technology, created in November 2010, has greatly facilitated the
financial and administrative management of the research projects, namely the submission of payment requests, previously
submitted and sent in paper.
Orders and reception of goods and services
All requisitions of goods and services and equipment maintenance are administratively verified, daily and before sending to the
supplier, also the reception is administratively verificated. The reception of goods and the respective invoices are conciliated before
payment.
The General Secretary also support the maintenace and renewal of the IPATIMUP's library.
Financial movements’ management
At the weekly meeting of the Coordinator Council, it is analyzed all the internal management requests, the payments and
transference of funds, the proposals for equipment acquisition and the proposals for opening of internal accounts. All the approved
movements are later launched in the backoffice accounts.
Helpdesk
The implementation of this instrument began in 2009 and continues to be the key to solve technical problems that arise from the
various equipments and infrastructures existing in the institution. Upon reception and resolution of tickets by the technical
supervisor, the entire documentation is delivered to the Secretariat, for archiving and closing the tickets.
Human resources
The internal management program has started in 2010 and has been a good tool for internal management of Human Resources.
Th administrative services receives and instructs all requests for personal entries, renewals or voluntary trainings. The requests are
latter submitted to a board member for authorization. In late 2011 this process began to be carried out electronically through
worflows created for this purpose.
77
Organization of events
Over the years IPATIMUP has been organizing two annual mettings, Portugaliae Genetica and Porto Cancer Meeting. The General
Secretary takes charge of the all organization and specific funding, togheter with the scientific organizing committee. Each year the
number of participants has been increasing. The General Secretary also takes charge of the organization of other events, as the PostDoc Symposiums. For the first time in 2011, the Post-Doc Forum has scientificly organized three Symposiums, with external speakers
and open to the entire scientific community. Also for the first time, we had in 2011 the I Workshop on Cancer Research, with a large
number of registrations.
Backoffice
The General Secretary is responsible for registering and updating all the information in the backoffice: personnel, events, internal
accounts, requisitions, projects, news, papers... Some of the files are for internal or external disclosure. This insertion and updating
of information is the source of the contents of the IPATIMUP webpage and IPATIMUP intranet.
A special note for the electronic archive of published scientific papers and the print exposition at the main hall of IPATIMUP. Since
September 2011, we have a scientific agenda and all the activities carried out in our facilities are announced in our web site and in
our Institute entrance.
ACTIVITY STATISTICS
Acconting Movements
Journals Reports
Cash:
Banks Integration:
Banks:
Collection of Revenue:
Documents Processed in the Accounting System:
Person Managment:
Employees Created:
Fixed Assets:
Files of Goods Created:
Human Resources
New Admission:
Updated:
Administrative / Financial Managment:
Number of financial requests:
Number of documents scanned and imported:
New Projects:
Maintenance:
Number of Tickets Closed:
Records
763
1.309
2.056
1.294
11.491
Records
18
Records
78
102
206
73
3.106
50
274
QUALITY CONTROL
Audits
The funding agencies demands regularly audit actions on the financial reports of projects. 2011 was an untypical year, once we had
just one audit for a project funded by the EEA Financial Mechanism. The results of this and previous audits have been validating
entirely the reported expenses.
78
PROGRAMS OFFICE
OVERVIEW
The Programs Office main tasks are to search and announce funding opportunities, and to support the submission of project
proposals and other research related programs and activities.
HIGHLIGHTS
During the year 2011, the office announced hundreds of funding opportunities such as projects, awards, fellowships and job
positions; it supported the submission of over 220 research project proposals (88% to national funding programs, 79% of which to
FCT (in its majority to the 2010 call for proposals to projects in all scientific domains) and 12% to international agencies, 10% of which
to European Commission programs, the majority to FP7) and also supported other scientific research related programs, which are
included in the regular activities of the institutes, such as licensing projects that involve animal experimentation, by the National
Authority DGV.
Along with the main activities, this office received and handled several requests for information and support from the researchers
and sent all sort of information concerning scientific meetings, workshops, conferences and seminars in & out the institutes.
OTHER ACTIVITIES
Like in previous years, the responsible for the office attended information sessions about the 7th Research Framework Program
(European Commission’s Research & Development Funding Program) and other research funding programs. In June, she attended
the “17th Annual EARMA Conference – Supporting and Sustaining Competitive Research in Europe”, organized by EARMA, that took
place in Bragança.
The Programs’ Office also had a relevant role in the coordination of the relations between the 3 institutes, concerning the I3S
Workshops and other information and diffusion activities.
79
ANNEXES
80
RECENT PHD
1.
Hugo Prazeres
Molecular and functional changes in familial thyroid cancer
Faculty of Medicine, Porto University (Supervisor Paula Soares)
2.
Ana Costa
Helicobacter pylori and epithelial tight junctions: exploring the interaction between bacteria and junctional adhesion
molecule
Faculty of Medicine, Porto University (Supervisors Céu Figueiredo; John Atherton, Nottingham University, UK)
3.
Nuno Guimarães
On the routes of Helicobacter pylori transmission
Center of Biological Engeneering, Minho University (Supervisors Céu Figueiredo; M.J. Vieira, U. Minho)
4.
Joana Caldeira
Factors that contribute to the malignant transformation of E-cadherin mutant cells in HDGC: a study in drosophila, cell
culture and tumours
Faculty of Medicine, Porto University (Supervisors Raquel Seruca; Fernando Casares, IBMC/ CABD-Centro Andaluz de
Biología del Desarrollo)
5.
João Miguel Sotto Maior Faria Carneiro
The role of non-coding DNA structural information in phylogeny, evolution and disease
Faculty of Sciences, Porto University (Supervisor António Amorim; Maria João Ramos, Faculty of Sciences, Porto
University)
6.
Sara Alexandra Vinhas Ricardo
Identifying Cancer Stem Cells in Breast Tumours: Searching for Cancer Origins”
Institut of Biomedical Sciences Abel Salazar, Porto University (Supervisors Joana Paredes, Fernando Schmitt)
7.
Helena Isabel Martins Pópulo
Relevance of mTOR pathway in the initiation/progression of human tumours
Faculty of Medicine, Porto University (Supervisors Paula Soares, José Manuel Lopes)
8.
Rui Manuel Lebreiro Pereira
Bridging the gap between SNPs and STRs: Insertion deletion polymorphisms in forensic genetics; principles and
applications
Faculty of Medicine, Santiago de Compostela University (Supervisors Leonor Gusmão; Ángel Carracedo, Santiago de
Compostela University)
9.
Ana Maria Rodrigues Leite de Magalhães
Characterization of molecular mechanisms relevant for Helicobacter pylori adhesion mediated by glycoconjugates
expressed in gastric mucosa.
Faculty of Medicine, Porto University (Supervisors Celso Reis; Thomas Borén, Umea University, Sweden)
10. Ana Sofia Pais Ribeiro
Does P-cadherin expression interfere with E-cadherin function in breast cancer cells?
Faculty of Medicine, Porto University (Supervisors Fernando Schmitt, Joana Paredes)
11. António Carlos Ferreira
Notch signalling pathway in gastric carcinogenesis: E-cadherin inactivation on Notch-dependent cell survival
Faculty of Medicine, Porto University (Supervisor José Carlos Machado)
81
12. Ana Rita F. P. Quental
Molecular and Evolutionary Perspectives on the Glycosylation Pathway
Faculty of Sciences, Porto University (Supervisor António Amorim)
13. Verónica Daniela Ramos Gomes
Ethnicity and Genetics in sub-Saharan Africa
Faculty of Medicine, Santiago de Compostela University (supervisor Leonor Gusmão; Ángel Carracedo, Santiago de
Compostela University, Paula Sánchez Diz, Santiago de Compostela University)
14. Andreia Filipa dos Santos Palmeira
Design, synthesis and evaluation of xanthone derivatives for dual activity: antitumor and P-glycoprotein inhibition"
Faculty of Pharmacy, Porto University (supervisors Helena Vasconcelos, Emília Sousa and Madalena Pinto, Faculty of
Pharmacy, Porto University)
15. Hugo Pinheiro
E-cadherin: New Regulatory Mechanisms in Cancer
Faculty of Medicine, Porto University (Supervisor Carla Oliveira)
82
RESEARCH PROJECTS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
Genetic and chronological characterisation of the European settlement by modern humans in the Upper Palaeolithic [FCT]
MUC1 protein - a new approach to target pancreatic cancer stem cells [IPATIMUP]
Portuguese Wild Mushrooms: Chemical characterization and functional study of antiproliferative and proapoptotic
properties in cancer cell lines [FCT]
A European Initial Training Network on the History, Archaeology, and New Genetics of the Trans-Atlantic Slave Trade [EU]
A strategy for preventing H.pylori-associated gastric cancer based on materials with specific receptors to the bacterinform SAMS to Gly-R chitosan microspheses [FCT]
A Study of the antitumour potential of three Portuguese Wild Mushrooms [Universidade do Porto]
Acção dos ácidos gordos polinsaturados n-3 na modulação do processo da inflamação e tumorigénese [CRUP]
Aging genes in model and non-model organisms a comparative approach [IPATIMUP]
Alterações metabólicas e cancro: GRIM-19 um gene do metabolismo celular e um gene supressor tumoral, que poderá ser
um target terapêutico interssante [Merck]
An approach to thyroid cancer targeted-therapy using transgenic zebrafish as a model [IPATIMUP]
Analysis of the function and mechanisms of action of a novel Wnt pathway member in vertebrate tumourigenesis and
development [IPATIMUP]
Approaching basal-like breast carcinomas to target therapy. A project combining the reinforcement of logistic facilities
with translational research [IPATIMUP]
Are genetic polymorphisms in inflammatory molecules risk factors for the development of autoimmune thyroiditis? (This
project implies the establishment of a tumour database) [IPATIMUP]
Bacterial protein azurin as a new candidate drug to trat poor-prognosis breast cancer [FCT]
Banco de Tumores - Amostras Congeladas [IPATIMUP]
Basal-like Breast Cancer: are mammary stem cells new targets for cancer therapy? [FCG]
Cancer risk and irradiation: an epidemiological and genetic study of a cohort irradiated for Tinea Capitis [FCT]
Cancro-Educar para prevenir [Alto Comissariado da Saúde]
CDX2 autoregulation in the reversibility/irreversibility of gastric intestinal metaplasia [FCT]
CDX2-induced alterations of the gastric glycoproteome [IPATIMUP]
Challenges in target-based therapy: Mechanisms of resistance to trastuzumab in her2-overexpressing breast carcinomas
[IPATIMUP]
Characterization of voriconazole susceptibility in relevant clinical molds [Pfizer]
Charaterization of the 17q21microdeletion-predisposing inversion polymorphism in the Portuguese population
[IPATIMUP]
Co-Evolutionary Study of Nad Biochemical Networks [FCT]
Colonization, inflammation and infection on Portuguese cystic fibrosis patients [FCG]
Comparative analysis of DNA sequence evolution in nuclear and mitochondrial backgrounds in inbreb mice [IPATIMUP]
Computational disease prediction systems based on molecular markers [FCT]
Conhecer a doença: Os doentes em primeiro lugar [FCG]
Cooperação Portugal/França Programa Pessoa 2011-2012 [FCT]
Criação de um Banco de DNA e RNA acoplado ao Banco de Tecidos e Tumores do H. S. João [IPATIMUP]
Description and analysis of genetic polymorphism in micro-ruminants [IPATIMUP]
Desenvolvimento de um novo método de detecção de mutações com relevância preditiva na resposta de doentes com
carcinoma colo rectal ao tratamento com cetuximab [ADI - Programa IDEIA]
Desenvolvimento de um sistema de informação médica sobre Cancro Hereditário da Mama e Colorectal [FCT]
Determining the CCAAT/enhancer binding protein ß (C/EBPß) partnership profile in gastric carcinogenesis [IPATIMUP]
Development of siRNA-loaded nanoparticles to circumvent chemoresistance in cancer stem cells [FCT]
Development of tools for automatic comparison of biological sequences [IPATIMUP]
Discovery of novel cancer serum biomarkers based on aberrant post translational modifications of O-glycoproteins (OPTM-Biomarkers) and their application to early detection of cancer [EU]
Disorders on the Glycolytic and Pentose Phosphate Pathaways of the Red Blood Cell - how do they affect Plasmodium
infection? Population Genetics IHMT 2011-04-01 2013-04-01 24 3840
VMLIS GRIM-19, a novel protein involved in cell apoptosis: structure-function characterization" [FCT]
Dissecção molecular do fenótipo de multinucleaçao das células de Hodgkin: validação de resultados [IPATIMUP]
Dissection of the molecular role of O-GLcNAc in the multinucleation phenotype of the neoplasic cells in Hodgkin´s
lymphoma [FCT]
DOENÇA DE FABRY: PATOGÉNESE E HISTOPATOLOGIA [Genzyme]
Does P-cadherin expression interfere with E-cadherin function in invasive breast cancer cells? [IPATIMUP]
Early detection of cancer using serum biomarkers based on aberrant post-translational modifications of O-glycoproteins,
O-PTM-Biomarkers [FCT]
E-cadherin Post-Translational Modifications by N-glycosylation: a potencial new mechanism of E-cadherin deregulation in
cancer [FCT]
83
46. Effect of radio-and chemotherapy on cancer cell invasion: the role of macrophages [FCT]
47. Estudo do papel dos microRNAs como co-reguladores do complexo da desidrogenase dos alfacetoácidos ramificados
[IPATIMUP]
48. Ethnicity and genetics in Sub-Saharan Africa [IPATIMUP]
49. Evaluation and Control of Neglected Mucosal Enteric Infections in Childhood [EU]
50. Evaluation of the structural impact of CPS1 variants using a homology modelling strategy [IPATIMUP]
51. Evaluation the role of proteolysis in the male reproductive system through the study of KLK (19q13,4) and WFDC (20q13)
gene clusters [IPATIMUP]
52. Exploring the role of E-cadherin trafficking deregulation in epithelial cancer progression [FCT]
53. Exploring the role of E-Cadherin-HER interaction in the search of molecular biomarkers for the clinical management of
gastric cancer patient [FCT]
54. Fellowship para apoio ao Internato de Anatomia Patológica no Hospital de S. João [FCG]
55. Function studies of Germline Missense mutations in HDGC Families [IPATIMUP]
56. Functional and molecular characterization of Daphnia longevity genes [IPATIMUP]
57. Galectin-3 interaction with cancer-associated MUC1 can regulate canine mammary tumour cell endothelial adhesion thus
promoting metastasis [IPATIMUP]
58. Galectins as modulators of tumor progression:Establishement of anti-cancer action of bioactive fragments from pectin by
inhibiting galectin - 3 [IPATIMUP]
59. Genetic analysis of 15STR loci in the population of the Acre province, Northern Brazil [IPATIMUP]
60. Genetic and chronological characterisation of the European settlement by modern humans in the Upper Palaeolithic
[IPATIMUP]
61. Genetic of populations of jewis origin [IPATIMUP]
62. Glycosylation alterations in cancer - characterization by proximity ligation (PLA) Assays and by production of glycopeptide
specific monoclonal antibodies [IPATIMUP]
63. Helicobacter pylori diversity in pathogenesis, antibiotic resistance, and evasion from natural and vaccine-induced immune
responses (HELDIVPAT) [FCT]
64. Helicobacter pylori genetic variation in virulence factors: An opportunity to identify individuals at increased risk for
disease [IPATIMUP]
65. Identificação de factores prognósticos e de selecção terapêutica em carcinomas diferenciados da tireoide [FCG]
66. Identificação de vias de sinalização mediadas pelo oncogene MUC1 em linhas celulares de carcinoma gástrico e em células
gástricas imortalizadas [FCT]
67. Identification of a susceptibility locus for gastric cancer in the IL1 gene cluster region [CRUP]
68. Identification of a susceptibility locus for gastric carcinoma in the IL1 gene cluster region [IPATIMUP]
69. Identification of Genetic markers for prediction of the clinical course and development of complications in portuguese
Crohn's Disease patients [GEDII]
70. Identification of SNP backgrounds of the Androgen Receptor gene: an attempt to understand AR diversity and the
mechanisms of instability underlying CAG and GGC coding repeats [IPATIMUP]
71. In Vitro characterization of cancer stem cell features mediated by P-cadherin expression in cancer cell lines and primary
carcinomas of the breast [IPATIMUP]
72. Integrated Micro-Nano-OPTO Fluidic systems for high-content diagnosis and studies of rare cancer cells [EU]
73. Interacção entre Helicobacter pylori e as junções intercelulares de aclusão [IPATIMUP]
74. Interaction of HER receptors (EGFR and HER2) and E-Cadherin. Search of molecular biomarkers for clinical management of
gastric cancer patients [Roche]
75. Is the mTOR pathway relevant in the initiation/progression and/or a putative therapeutic target in melanomas?
[IPATIMUP]
76. Laboratório Aberto [Câmara Municipal do Porto]
77. Large inversion polymorphisms in the human genome [IPATIMUP]
78. Leonese dialects in Portugal: a genetic approach to a historical-linguistic issue [IPATIMUP]
79. Looking for evidences of human adaptation in the proteolysis universe: the case-study of serine protease inhibitors [FCT]
80. Males lineages in South Amerindian populations [IPATIMUP]
81. miRNAs como alvos moleculares em leucemia humana [FCG]
82. MLK3, um novo gene mutado em cancro colorectal com instabilidade de microssatélites [FCT]
83. Modelos de Sistemas de Gestão do Risco na Investigação em Ciências da Vida e da Saúde [ON]
84. Modulation of H-RAS alternative splicing and oncogenic activity; role of the 81T/C polymorphism [IPATIMUP]
85. Molecular and nanotecchnology-based approaches to improve the antitumor activity of small molecules [FCT]
86. Molecular diagnosis of OTC deficienty: too many unsolved cases [FCT]
87. mTOR expression in breast carcinomas and the ability of everolimus (RAD 001) to modulate its expression [Novartis
Farma]
88. Mucin MUC16-CA125 cancer biomarker - biological functions and development of biomarker assays [IPATIMUP]
89. Mutated suppressor tRNAs as a therapeutic tool for cancer associated syndromes: HDGC as a model [FCG]
90. New E-cadherin RNAs: the dark side of a tumour suppressor gene [FCT]
91. non-coding DNA structural information in phylogeny, evolution and disease [IPATIMUP]
84
92. O contributo de factores genéticos e não genéticos para a diversidade fenotipica dos doentes com fenilcetonúria: um
estudo baseado no Programa Português de Rastreio Neonatal [FCT]
93. O Nemátode-Da-Madeira-Do-Pinheiro (NMP), Bursaphelenchus Xyliophilus [FCT]
94. Origin, evolution and functional divergence of ataxin-3 paralogs: ATXN3L1 and ATXN3L2 [IPATIMUP]
95. P-cadherin overexpression: an alternative mechanism for E- Cadherin loss-of-function in invasive human carcinomas
[IPATIMUP]
96. Pharmacogenetics [IPATIMUP]
97. PIK the Fraternity [IPATIMUP]
98. Polimorfismos em genes de moléculas pro-inflamatórias e risco de tireoidite de Hashimoto [Universidade do Porto]
99. Prestação de Serviços para desenvolvimento da aplicação informática para gestão da base de dados da futura Rede
Nacional de Banco de Tumores [Alto Comissariado da Saúde]
100. Prevention and early diagnosis of cancer [EEAGRANTS]
101. Primary hyperparathyroidism - from geneside to bedside [IPATIMUP]
102. Programa de Acções Integradas Luso-Francesas PAULIF2011 [CRUP]
103. Programa de Apoio à Pós-Graduação em Anatomia Patológica [IPATIMUP]
104. Projecto de Desenvolvimento e Implementação de um modelo de ensino inclusivo da Ciência numa população de alunos
cegos ou com baixa visão [FCG]
105. Protein glycosylation in epithelial cells: A glycomic approach to unravel cancer-related glycostructures [IPATIMUP]
106. Regulation of P-cadherin Expression in Breast Cancer [IPATIMUP]
107. Research launching in Aspergillus fumigatus genetics [IPATIMUP]
108. Research launching in biomarkers research [IPATIMUP]
109. Research launching in fungal models [IPATIMUP]
110. S1H-RAS expression and activity regulation;implications in tumorigenesis [IPATIMUP]
111. Search for genomic structural variants in azoopermia:a study in the Portuguese population [FCT]
112. Single-molecule analysis of cadherin-mediated cell-cell adhesion [NIH]
113. Sorting out the genetics of neuroendocrine tumours [IPATIMUP]
114. SOX2 and CDX2 negative cross-regulation in the establishement of intestinal metaplasia of the stomach [IPATIMUP]
115. SOX2 and CDX2 negative cross-regulation in the establishment of intestinal metaplasia of the stomach [IPATIMUP]
116. Study of mTOR pathway in GISTs [Novartis Farma]
117. Study of mTOR pathway in human cancer [IPATIMUP]
118. Study of SDH alterations in GIST [IPATIMUP]
119. Study of the role played by TGF-B dual effect in the progression of papillary thyroid carcinoma [Genzyme]
120. Targeting the Warburg effect for cancer therapy [IPATIMUP]
121. Telepathological Assessment of histopathological and cytological techniques [EU]
122. The causes and consequences of mitochondrial DNA deletions in animals cells [FCT]
123. The genetic diversity in populations of the African sahel: from population genetics to the study of associations to complex
diseases and traits [IPATIMUP]
124. The genetic impact of agropastoral dispersals in Sub-Saharan Africa [IPATIMUP]
125. The involvement of CDH1 in CG angiogenesis [IPATIMUP]
126. The involvement of microRNAs in gastric cancer [IPATIMUP]
127. The role of protein quality control in cancer [IPATIMUP]
128. The Role of Protein Quality Control in the regulation of E-cadherin and its relevance in cancer [FCT]
129. Transcriptional and post-transcriptional mechanisms of LRP1B inactivation in sporadic and familial non-medullary thyroid
cancer [FCT]
130. Tumour spectrum in hereditary Diffuse Gastric Cancer [FCT]
131. Tumour spectrum in hereditary Diffuse Gastric Cancer [IPATIMUP]
132. Uncovering novel oncogenic signaling properties of BRAF in human cancers [IPATIMUP]
133. Unraveling the genetics of neuroendocrine tumors by high throughput methods [IPATIMUP]
134. Unveiling GRIM-19 functional roles in cancer metabolism [IPATIMUP]
135. Urease de helicobacter pylori: propriedades não enzimáticas que potencialmente contribuem para gastrite e cancro
gástrico [FCT]
136. Vitamin D, a candidate for new therapy of basal-like breast carcinomas [FCT]
137. X chromosone and autosomal indel markers in kinship analysis [IPATIMUP]
85
SCIENTIFIC PAPERS
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Santos LF, Pereira T, Rodrigues B, Correia E, Moreira D, Nunes L, Costa A, Elvas L, Machado JC, Castedo S, Henriques C,
Matos A, Oliveira S. Critérios de diagnóstico da Síndrome de Brugada. Podemos melhorar?. Revista española de
cardiología: 1, 2011 [] [] [IF=2,157]
Leite M, Figueiredo C. The use of short-term human primary gastric epithelial cell cultures for studying Helicobacter pylori
infection. Methods in molecular biology (Clifton, N.J.): 1, 2011 [] [] [IF=0]
Albergaria A, Ribeiro A S, Vieira AF, Sousa B, Nobre AR, Seruca R, Schmitt F, Paredes J. P-cadherin role in normal breast
development and cancer.. International Journal Dev Biology: 811-822, 2011 [10.1387/ijdb.113382aa] [] [IF=0]
Ribeiro AS, Sousa B, Carreto L, Mendes N, Ricardo S, Albergaria A, Cameselle-Teijeiro JF, Gerhard R, Soderberg O, Seruca
R, Santos MA, Schmitt F, Paredes J. P-cadherin promotes cancer cell invasion by interference with E-cadherin suppressor
function. The FASEB Journal: 1, 2011 [] [] [IF=6,515]
Manta F, Caiafa A, Pereira R, Silva DA, Amorim A, Carvalho EF, Gusmão L. Indel markers: genetic diversity of 38
polymorphisms in Brazilian populations and application in a paternity investigation with post mortem material. Forensic
Sci Int: Genetics: 1, 2011 [] [] [IF=2,877]
Peleteiro B, Lunet N, Xiaogang W, Afonso LP, Mendes N, Barros R, Carneiro F, Almeida R, Barros H. Association between
environmental factors and CDX2 expression in gastric cancer patients. European Journal of Cancer Prevention: 1, 2011 []
[] [IF=2,536]
Ricardo S, Gerhard R, Cameselle-Teijeiro JF, Schmitt F, Paredes J. Claudins Expression in Breast Cancer: High or Low, What
to Expect?. Histology and histopathology: 1, 2011 [] [Meeting Abstract] [IF=2,502]
Vieira AF, Ricardo S, Ablett MP, Dionísio MR, Mendes N, Albergaria A, Farnie G, Gerhard R, Cameselle-Teijeiro JF, Seruca R,
Schmitt F, Clarke R, Paredes J. P-cadherin is co-expressed with CD44 and CD49f and mediates stem cell properties in basallike breast cancer. Stem Cells: 1, 2011 [] [] [IF=7,871]
Oliveira P, Sanges R, Huntsman DG, Stupka E, Oliveira C. Characterization of the intronic portion of cadherin superfamily
members, common cancer orchestrators. European journal of human genetics : EJHG: 1, 2011 [] [] [IF=4,38]
Martins E M., Vilarinho L, Esteves S, Lopes-Marques M, Amorim A, Azevedo L. CONSEQUENCES OF PRIMER BINDING-SITES
POLYMORPHISMS ON GENOTYPING PRACTICE. Open Journal of Genetics: 15-17, 2011 [10.4236/ojgen.2011.12004] []
[IF=0]
Pinho S S, Oliveira P, Cabral J, Carvalho S, Hustman D, Seruca R, Reis C, Oliveira C. Loss and recovery of Mgat3/GnT-III
mediated E-cadherin N-glycosylation is a mechanism involved in Epithelial-Mesenchymal and Mesenchymal-Epithelial
Transitions. PloS one: 1, 2011 [] [] [IF=4,411]
Costa N, Paulo P, Caffrey T, Hollingsworth MA, Santos-Silva F. Impact of MUC1 mucin downregulation in the phenotypic
characteristics of MKN45 gastric carcinoma cell line. PloS one: 1, 2011 [] [] [IF=4,411]
Bobillo C, Sala A, Gusmão L, Corach D. Genetic analysis of 10 X-STRs in Argentinian population. Forensic science
international. Genetics: 14-16, 2011 [10.1016/j.fsigen.2009.11.005] [] [IF=2,877]
Nunes A C S, Silva D, Teixeira M A D, Nunes D D., Lopes C M.S., Tucunduva Netto O R., Gusmão L, Carvalho E F., Moura M
M F.. Y chromosome comparative analysis of Rondônia with other Brazilian populations. Elsevier Science: 13: 161-163,
2011 [10.1016/j.legalmed.2010.12.007] [] [IF=0]
Martinez B, Builes J J., Gusmão L, Manrique M, Aguirre D, Puerto Y, Caraballo L, Bravo M L. Genetic data of 10 X-STR in a
Colombian population of Bolivar Department. Elsevier Science: 3: 59-60, 2011 [10.1016/j.fsigss.2011.08.029] [] [IF=0]
Vullo C, Borosky A, Catelli M, Romanini C, Fondevila M, Santos C, Pereira R, Gusmão L. Population data for 38 autosomal
insertion/deletion (InDels) and 50 SNPS polymorphisms in Argentinean population. Elsevier Science: 3: 419-420, 2011
[10.1016/j.fsigss.2011.09.071] [] [IF=0]
Magalhães M, Pinto N, Gomes C, Pereira R, Amorim A, Alves C, Gusmão L. When the alleged father is a close relative of
the real father: The utility of insertion/deletion polymorphisms. Elsevier Science: 3: 9-10, 2011
[10.1016/j.fsigss.2011.08.004] [] [IF=0]
Costa N, Sousa A, Teixeira C, Castro J, Guimarães N, Santos-Silva F. Oncogenic signaling in gastric cancer. IntechOpen: 1,
2011 [] [] [IF=0]
Brito P, Carvalho M, Gomes V, Melo MM, Bogas V, Balsa F, Andrade L, Serra A, Lopes V, Gusmão L, Anjos MJ, Corte-Real F.
Y-SNP analysis in an Angola population. Elsevier Science: 369-370, 2011 [10.1016/j.fsigss.2011.09.046] [] [IF=0]
Restrepo Tomás, Martinez M, Palacio Oscar, Posada Y, Zapata S, Gusmão L, Ibarra A. Database sample size effect on
minimum allele frequency estimation: Database comparison analysis of samples of 4652 and 560 individuals for 22
microsatellites in Colombian population. Elsevier Science: 13-14, 2011 [10.1016/j.fsigss.2011.08.006] [] [IF=0]
van Asch B, Pereira R, Carneiro J, Amorim A. Population assignment in seven Portuguese dog breeds and Iberian wolves.
Elsevier Science: 3: 556-557, 2011 [10.1016/j.fsigss.2011.10.019] [] [IF=0]
Magalhães M, Pinto N, Gomes C, Pereira R, Amorim A, Alves C, Gusmão L. When the alleged father is a close relative of
the real father: the utility of insertion/deletionpolymorphisms. Forensic Sci Int: Genetics: 1, 2011
[doi:10.1016/j.fsigss.2011.08.004] [] [IF=2,877]
Damas J, Amorim A, Gusmão L. InDels in Y chromosome haplogroup definition. Forensic Sci Int: Genetics: 178-179, 2011
[10.1016/j.fsigss.2011.08.089] [] [IF=2,877]
Pereira V, Moncada E, Diez IE, Tomas C, Amorim A, Morling N, Gusmão L, Prata MJ. Genetic characterization of Somali and
Iraqi populations using a set of 33 X-chromosome Indels. Forensic science international. Genetics: 1, 2011
[10.1016/j.fsigss.2011.08.069] [] [IF=2,877]
Caldeira J, Simões-Correia J, Paredes J, T Pinto M, Sousa S, Corso G, Roviello F, S Pereira P, Weil D, Oliveira C, Casares F,
Seruca R. CPEB1, a novel gene with anti-angiogenic potential, is silenced in Gastric Cancer. Gut: 1, 2011 [] [] [IF=10,614]
86
26. Soares P, Lima J, Preto A, Castro P, Vinagre J, Celestino R, Couto JP, Prazeres H, Eloy C, Máximo V, Sobrinho-Simões M.
Alterations in Poorly Differentiated and Unddiferentiated Thyroid Carcinomas. Current genomics: 1, 2011 [] [] [IF=2,487]
27. Cameselle-Teijeiro J, Ferreira R, Caramés N, Abdulkader I, Máximo V, Soares P, Sobrinho-Simões M. Absence of both the
BRAF and the GRIM-19 mutations in oncocytic (Hürthle cell) solid cell nests of the thyroid. American journal of clinical
pathology: 1, 2011 [] [] [IF=2,504]
28. Soares I, Amorim A, Goios A. A new algorithm for mtDNA sequence clustering. Elsevier Science: 315-316, 2011
[10.1016/j.fsigss.2011.09.020] [] [IF=0]
29. Pinto N, Gusmão L, Silva PV, Amorim A. Estimating coancestry from genotypes using a linear regression method. Elsevier
Science: 373-374, 2011 [10.1016/j.fsigss.2011.09.048] [] [IF=0]
30. Pinto N, Gusmão L, V. Silva P, Amorim A. Estimating coancestry from genotypes using a linear regression method. Forensic
Sci Int: Genetics: 3: 373-e374, 2011 [] [] [IF=2,877]
31. Pinto N, Gusmão L, Egeland T, V. Silva P, Amorim A. Estimation of Coancestry Coefficient from Genotypic Data: a Revision
of the AutosomalCase and Extension to X-chromosome Markers. PloS one: 1, 2011 [] [] [IF=4,411]
32. Martins S, Soong B-W, Wong VCN, Giunti P, Stevanin G, Ranum LPW, Sasaki H, Riess O, Tsuji S, Coutinho P, Amorim A,
Sequeiros J, Nicholson GA. Is a new mutational origin responsible for Machado-Joseph disease in the Australian aboriginal
communities of Groote Eylandt and Yirrkala?. Arch Neurol: 1, 2011 [] [] [IF=0]
33. Gonçalves MJ, Mendes NM, João F, Lopes JM, Honovar M. Primary peomorphic sarcoma of lung-11 year survival. Revista
portuguesa de pneumologia: 1, 2011 [] [] [IF=0,355]
34. Morais P, Mota A, Eloy C, Lopes JM, Torres F, Palmeiro A, Tavares P, Azevedo F. Vascular Ehlers-Danlos syndrome: a case
with fatal outcome. Dermatology online: 1, 2011 [] [] [IF=2,714]
35. Schmitt F, Barroca H. Possible use and role of molecular techniques in fine-needle aspiration cytology (FNAC) pratice.
Diagnostic Histopathology: 17: 286-292, 2011 [] [] [IF=0]
36. Cochand-Priollet B, Schmitt F, Totsch M, Vielh P. The Bethesda Terminology for Reporting Thyroid Cytopathology: from
theory to practice in Europe. Acta cytologica: 55: 507-511, 2011 [10.1159/000334687] [Article] [IF=0,647]
37. Gomes C, Magalhães M, Amorim A, Alves C, Pinto N, Gusmão L. How useful is your X in discerning pedigrees?. Forensic Sci
Int: Genetics: 1, 2011 [doi:10.1016/j.fsigss.2011.08.081] [] [IF=2,877]
38. Montesino M, Tagliabracci A, Zimmerman B, Gusmão L, Burgos G, Heinrichs B, Prieto V, Paredes M, Hernandez A, Cardoso
S, Vullo C, Marino M, Whittle M, Velazquez M, Sanchez-Simon M, Maxud K, Anjos M J, Vargas - Diaz L E, Lopez-Parra AM,
Bobillo B, Garcia-Segura R, Puente J, Pedrosa S, Streitenberger ER, Moreno F, Chemale G, Pestano J, Merigioli S, Espinoza
M, Comas D, Lopes-Cubria CM, Bogus M, Prieto L, Parson W. GHEP-ISFG Proficiency Test 2011: Paper challenge on
evaluation of mitochondrial DNA results. Elsevier Science: 545-547, 2011 [10.1016/j.fsigss.2011.10.015] [] [IF=0]
39. Builles JJ, Aguirre D, Manrique A, Puerto Y, Bravo ML, Gaviria A, Gutierrez A, Munoz M, Fonseca D, Usaquen W, Castillo A,
Pineda C, Ugalde N, Cicarelli RMB, Ibarra A, Trejos DM, Hudy LD, De Castro M, Diaz LF, Quiceno D, Pinzon A, Gavilan M,
Sanchez D, Roa M, Ossa H, Ianaconne G, Mendonza L, Ruiz M, Solis L, Ruiz M, Solis L, Pareja L, Guevara A, Carracedo A,
Gusmão L. Colombian results of the interlaboratory Quality Control Exercise 2009–2010. Elsevier Science: 3: 57-58, 2011
[10.1016/j.fsigss.2011.08.028] [] [IF=0]
40. Pereira V, Tomas Carmen, Sanchez Juan, Amorim A, Gusmão L, Prata MJ, Morling Niels. Study of 25 X-chromosome Single
Nucleotide Polymorphisms in African and Asian populations. Elsevier Science: 139-140, 2011
[10.1016/j.fsigss.2011.08.070] [] [IF=0]
41. van Asch B, Amorim A, Pereira F, Santos L S, Carneiro J. Mitochondrial lineages reveal intense gene flow between Iberian
wild boars and South Iberian pig breeds. Animal Genetics: 1, 2011 [10.1111/j.1365-2052.2011.02222.x] [Article]
[IF=2,203]
42. Vilarinho L, Esteves S, Ramos E, Amorim A, Azevedo L. PAH MUTATIONAL SPECTRUM: STILL EXPANDING. Open Journal of
Genetics: 1, 2011 [10.4236/ojgen.2011.12002] [] [IF=0]
43. Alvelos MI, Mendes M, Soares P. Molecular Alterations in Sporadic Primary Hyperparathyroidism. Genetics Research
International volume 2011: 1, 2011 [10.4061/2011/275802] [] [IF=0]
44. Milne AN, Offerhaus GJA, Carneiro F. Histopathology of familial and early-onset gastric cancer. Diagnostic Histopathology:
17: 62-68, 2011 [10.1016/j.mpdhp.2010.10.009] [] [IF=0]
45. Pereira R, Phillips C, Pinto N, Santos C, Santos SEB, Amorim A, Carracedo A, Gusmão L. Straightforward inferrence of
ancestry and admixture proportions through ancestry-informative insertion deletion multiplexing. PloS one: 1, 2011
[10.1371/journal.pone.0029684] [] [IF=4,411]
46. Coutinho F, Silva Santos L, Lacerda L, Quental MS, Wibrand F, Lund AM, Johansen KB, Prata MJ, Alves SC. Alu-Alu
recombination underlying the first large genomic deletion in GlcNAc-phosphotransferasealpha/beta (GNPTAB) gene in a
MLII alpha/beta patient. Journal of inherited metabolic disease: 1, 2011 [10.1007/8904_2011_83] [] [IF=3,808]
47. van der Werf C, Wabbersen T, Hsiao N, Paredes J, Etchevers H, Kroisel P, Tibboel D, Babarit C, Babarit C, Schreiber R,
Hoffenberg E, Vekemans M, Zeder S, Ceccherini I, Lyonnet S, Ribeiro Ana S., Seruca R, Meerman G, IJzendoorn S, Shepherd
I, Verheij J, Hofstra R. Mutations in CLMP cause Congenital Short Bowel Syndrome, pointing to its major role in intestinal
development. Gastroenterology: 1, 2011 [] [] [IF=12,032]
48. van Asch B, Pereira R, Carneiro J, Amorim A. Population assignment in seven Portuguese dog breeds and Iberian wolves.
Forensic Sci Int: Genetics: 556-557, 2011 [doi:10.1016/j.fsigss.2011.10.019] [] [IF=2,877]
49. Vaz J A, Almeida G, Ferreira I C.F.R., Martins A, Vasconcelos M H. Clitocybe alexandri extract induces cell cycle arrest and
apoptosis in a lung cancer cell line: identification of phenolic acids with cytotoxic potential. Food Chemistry: , 2011
[10.1016/j.foodchem.2011.11.031] [Epub ahead of print] [IF=3,458]
50. Tavares de Oliveira J, José de Matos A, Santos Ana L, Pinto R, Gomes J, Hespanhol V, Chammas R, Aki M, Bernardes E S.,
Reis C A, Rutteman G, Gartner F. Sialylation regulates galectin-3/ligand interplay during mammary tumour progression: a
case of targeted uncloaking.. International Journal Dev Biology: 823-834, 2011 [10.1387/ijdb.113359jt] [] [IF=0]
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51. Pinho S, Carvalho S, Cabral J, Reis C, Gartner F. CANINE TUMORS: A SPONTANEOUS ANIMAL MODEL OF HUMAN
CARCINOGENESIS. Translational Research: 1, 2011 [http://dx.doi.org/10.1016/j.trsl.2011.11.005,] [] [IF=2,903]
52. Costa A da, Kohn B, Oliveira JT, Gartner F, Gruber AD, Klopfleisch K. Genetic Markers for the Detection od Circulating
tumour cells in dogs with metastatic mammary tumours.. Journal of comparative pathology: 4: 143, 2011 [] [] [IF=1,529]
53. Cassali GD, Bertagnolli AC, Gartner F, Schmitt F. Canine mammary tumours: A quantitative DNA study using static
cytometry.. Revista Española de Patologia: 44: 195-201, 2011 [10.1016/j.patol.2011.05.005] [] [IF=0]
54. Pinto N, Amorim A. Identity-by-descent.. Brenner's Online Encyclopedia of Genetics 2E: 1, 2011 [] [] [IF=0]
55. Palmeira A, Sousa E, Fernandes MX, Pinto MM, Vasconcelos M H. Multidrug resistance reversal effects of aminated
thioxanthones and interaction with cytochrome P450 3A4.. Journal of Pharmacy & Pharmaceutical Sciences: 3: 31-45,
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56. Neves MP, Lima RT, Choosang K, Pakkong P, Nascimento MS, Vasconcelos MH, Pinto M, Silva AM, Cidade H. Synthesis of
natural chalcone and its prenyl-analogues - Evaluation of tumor cell growth inhibitory activity and effects on cell cycle and
apoptosis. Chemistry & Biodiversity: , 2011 [] [Epub ahead of print] [IF=1,586]
57. Celestino R, Lima J, Faustino A, Máximo V, Gouveia A, Vinagre J, Soares P, Manuel Lopes J. A novel germline SDHB
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58. Boaventura P, Oliveira R, Pereira D, Soares P, Teixeira-Gomes J. Head and neck basal cell carcinoma prevalence in
individuals submitted to childhood X-ray 1 epilation for tinea capitis treatment. European Journal of Dermatology: 1, 2011
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59. Otsoa FL, Rodriguez ES, Aillet F, Casado JV, Lang V, Matthiesen R, Elortza F, Rodriguez M. Integrative analysis of the
Ubiquitin Proteome Isolated using Tandem Ubiquitin Binding Entities (TUBEs). Journal of Proteomics: 1, 2011 [] []
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60. Vasconcelos M. Helena, Vaz Josiana A., Barros L, Martins A, Sá Morais J, Ferreira I C.F.R.. Phenolic profile of seventeen
Portuguese wild mushrooms. LWT - Food Science and Technology: I: 0, 2011 [10.1016/j.lwt.2010.06.029] [Article]
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61. Vaz J A., Barros L, Martins A, Santos-Buelga C, Vasconcelos M. Helena, Ferreira I C.F.R.. Chemical composition of wild
edible mushrooms and antioxidant properties of their water soluble polysaccharidic and ethanolic fractions. Food
Chemistry: 126: 610-616, 2011 [10.1016/j.foodchem.2010.11.063] [Article] [IF=3,458]
62. Kluijt I, Siemerink EJ, Ausems MG, van Os TA, de Jong D, Simões-Correia J, van Krieken JH, Ligtenberg MJ, Figueiredo J, van
Riel E, Sijmouns RH, Plukker JT, van Hillegersberg R, Dekker E, Oliveira C, Cats A, Hoogerbrugge N. CDH1-related hereditary
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64. Soares I, Amorim A, Goios A. A new algorithm for mtDNA sequence clustering. Forensic Sci Int: Genetics: 1, 2011 [] []
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65. Ferreira RM, Machado JC, Leite M, Carneiro F, Figueiredo C. The number of Helicobacter pylori CagA EPIYA C tyrosine
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66. Oliveira Moreira A, Almeida A, Costa S, Laffon B, Garcia-Lestón J, Pásaro E, Mendéz J, Teixeira JP. Genotyping an ALAD
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67. Simões Correira J, Figueiredo J, Lopes R, Stricher F, Oliveira C, Serrano L, Seruca R. E-cadherin destabilization accounts for
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68. López E, Matthiesen R, Ashman K, Mendieta J, Wesselink Jan-Jaap, Gómez-Puertas Paulino, Ferreira A. Functional
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70. Amorim A. A comment on "The hare and the tortoise: one small step for four SNPs, one giant leap for SNP-kind".. Forensic
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71. Nascimento E, Cerqueira E, Gusmão L. Population database defined by 13 autosomal STR loci in a representative sample
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72. Morling N, Schneider PM, Mayr W, Gusmao L, Prinz M. Authentication of forensic DNA samples.. Forensic science
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73. Pinto N, Gusmão L, Amorim A. X-chromosome markers in kinship testing: a generalisation of the IBD approach identifying
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74. Bartosch C, Vieira J, Teixeira MR, Lopes JM. Endometrial endometrioid adenocarcinoma associated with primitive
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75. Leite M, Corso G, Sousa S, Milanezi F, Afonso LP, Henrique R, Soares JM, Castedo S, Carneiro F, Roviello F, Oliveira C,
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77. Santos A, Lopes C, Marques RM, Amorim I, Ribeiro J, Frias C, Vicente C, Gärtner F, de Matos A. Immunohistochemical
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78. Cerný V, Mulligan CJ, Fernandes V, Silva NM, Alshamali F, Non A, Harich N, Cherni L, El Gaaied AB, Al-Meeri A, Pereira L.
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79. Peixoto A, Santos C, Pinheiro M, Pinto P, Soares MJ, Rocha P, Gusmão L, Amorim A, van der Hout A, Gerdes AM,
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Pertesi M, Narod S, Royer R, Costa MM, Lazaro C, Feliubadaló L, Graña B, Blanco I, de la Hoya M, Caldés T, Maillet P,
Benais-Pont G, Pardo B, Laitman Y, Friedman E, Velasco EA, Durán M, Miramar MD, Valle AR, Calvo MT, Vega A, Blanco A,
Diez O, Gutiérrez-Enríquez S, Balmaña J, Ramon y Cajal T, Alonso C, Baiget M, Foulkes W, Tischkowitz M, Kyle R,
Sabbaghian N, Ashton-Prolla P, Ewald IP, Rajkumar T, Mota-Vieira L, Giannini G, Gulino A, Achatz MI, Carraro DM, de
Paillerets BB, Remenieras A, Benson C, Casadei S, King MC, Teugels E, Teixeira MR. International distribution and age
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80. Rodrigues AH, Santos RI, Arisi GM, Bernardes ES, Silva ML, Rossi MA, Lopes MB, Arruda E. Oropouche virus experimental
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81. Pópulo H, Vinagre J, Lopes JM, Soares P. Analysis of GNAQ mutations, proliferation and MAPK pathway activation in uveal
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82. Gil da Costa RM, Oliveira JP, Saraiva AL, Seixas F, Faria F, Gärtner F, Pires MA, Lopes C. Immunohistochemical
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83. Coutinho MF, Encarnação M, Gomes R, da Silva Santos L, Martins S, Sirois-Gagnon D, Bargal R, Filocamo M, RaasRothschild A, Tappino B, Laprise C, Cury GK, Schwartz IV, Artigalás O, Prata MJ, Alves S. Origin and spread of a common
deletion causing mucolipidosis type II: insights from patterns of haplotypic diversity.. Clinical genetics: 80: 273-80, 2011
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84. Corso G, Velho S, Paredes J, Pedrazzani C, Martins D, Milanezi F, Pascale V, Vindigni C, Pinheiro H, Leite M, Marrelli D,
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85. Rodrigues MM, Rema A, Gärtner F, Soares FA, Rogatto SR, De Mour VM, Laufer-Amorim R. Overexpression of vimentin in
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86. Pópulo H, Soares P, Faustino A, Rocha AS, Silva P, Azevedo F, Lopes JM. mTOR pathway activation in cutaneous melanoma
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87. Pereira V, Tomas C, Amorim A, Morling N, Gusmão L, Prata MJ. Study of 25 X-chromosome SNPs in the Portuguese..
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88. da Costa A, Oliveira JT, Gärtner F, Kohn B, Gruber AD, Klopfleisch R. Potential markers for detection of circulating canine
mammary tumor cells in the peripheral blood.. Veterinary journal (London, England : 1997): 190: 165-8, 2011
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89. Carvalho M, Brito P, Bento AM, Gomes V, Antunes H, Costa HA, Lopes V, Serra A, Balsa F, Andrade L, Anjos MJ, Corte-Real
F, Gusmão L. Paternal and maternal lineages in Guinea-Bissau population.. Forensic science international. Genetics: 5:
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90. Prazeres H, Torres J, Rodrigues F, Pinto M, Pastoriza MC, Gomes D, Cameselle-Teijeiro J, Vidal A, Martins TC, SobrinhoSimões M, Soares P. Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the
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91. Lima RT, Nascimento MS, Seca H, Soares P, Vasconcelos MH. EBV interferes with the sensitivity of Burkitt lymphoma Akata
cells to etoposide.. Journal of cellular biochemistry: 112: 200-10, 2011 [10.1002/jcb.22920] [Article] [IF=3,122]
92. Prieto L, Zimmermann B, Goios A, Rodriguez-Monge A, Paneto GG, Alves C, Alonso A, Fridman C, Cardoso S, Lima G, Anjos
MJ, Whittle MR, Montesino M, Cicarelli RM, Rocha AM, Albarrán C, de Pancorbo MM, Pinheiro MF, Carvalho M, Sumita
DR, Parson W. The GHEP-EMPOP collaboration on mtDNA population data--A new resource for forensic casework..
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93. Badve S, Dabbs DJ, Schnitt SJ, Baehner FL, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J,
Rakha EA, Richardson AL, Schmitt FC, Tan PH, Tse GM, Weigelt B, Ellis IO, Reis-Filho JS. Basal-like and triple-negative
breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists.. Modern pathology
: an official journal of the United States and Canadian Academy of Pathology, Inc: 24: 157-67, 2011
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94. Peleteiro B, Lopes C, Figueiredo C, Lunet N. Salt intake and gastric cancer risk according to Helicobacter pylori infection,
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95. Pinho SS, Seruca R, Gärtner F, Yamaguchi Y, Gu J, Taniguchi N, Reis CA. Modulation of E-cadherin function and dysfunction
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96. Corso G, Pedrazzani C, Pinheiro H, Fernandes E, Marrelli D, Rinnovati A, Pascale V, Seruca R, Oliveira C, Roviello F. Ecadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer.. European journal of cancer
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97. Linacre A, Gusmão L, Hecht W, Hellmann AP, Mayr WR, Parson W, Prinz M, Schneider PM, Morling N. ISFG:
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98. Queiroz MJ, Calhelha RC, Vale-Silva LA, Pinto E, Almeida GM, Vasconcelos MH. Synthesis and evaluation of tumor cell
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99. Lima RT, Busacca S, Almeida GM, Gaudino G, Fennell DA, Vasconcelos MH. MicroRNA regulation of core apoptosis
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100. Barros R, da Costa LT, Pinto-de-Sousa J, Duluc I, Freund JN, David L, Almeida R. CDX2 autoregulation in human intestinal
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101. Costa-de-Oliveira S, Marcos Miranda I, Silva RM, Pinto E Silva A, Rocha R, Amorim A, Gonçalves Rodrigues A, Pina-Vaz C.
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102. Klopfleisch R, von Euler H, Sarli G, Pinho SS, Gärtner F, Gruber AD. Molecular carcinogenesis of canine mammary tumors:
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104. Soares P, Sobrinho-Simões M. Cancer: Small papillary thyroid cancers--is BRAF of prognostic value?. Nature reviews.
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105. Persson C, Canedo P, Machado JC, El-Omar EM, Forman D. Polymorphisms in inflammatory response genes and their
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106. Pinto M, Soares P, Ribatti D. Thyroid hormone as a regulator of tumor induced angiogenesis.. Cancer letters: 301: 119-26,
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107. Lebreiro A, Martins E, Almeida J, Pimenta S, Bernardes JM, Machado JC, Abreu-Lima C. Value of molecular diagnosis in a
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108. Eloy C, Vinagre J, Cameselle-Teijeiro J, Paiva ME, Soares P, Sobrinho-Simões M. Tumor-in-tumor of the thyroid with
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109. Schmitt F, Tötsch M, Vielh P. A letter yet to receive a reply.. Cytopathology : official journal of the British Society for
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112. Matthiesen R, Azevedo L, Amorim A, Carvalho AS. Discussion on common data analysis strategies used in MS-based
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114. Mendizabal I, Valente C, Gusmão A, Alves C, Gomes V, Goios A, Parson W, Calafell F, Alvarez L, Amorim A, Gusmão L,
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115. Yotova V, Lefebvre JF, Moreau C, Gbeha E, Hovhannesyan K, Bourgeois S, Bédarida S, Azevedo L, Amorim A, Sarkisian T,
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116. Santos A, Lopes C, Frias C, Amorim I, Vicente C, Gärtner F, Matos A. Immunohistochemical evaluation of MMP-2 and
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127. Soares S, Vitorino R, Oso´rio H, Fernandes A, Vena^ncio A, Mateus N, Amado F, de Freitas V. Reactivity of Human Salivary
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139. Ferreira Z, Hurle B, Rocha J, Seixas S. Differing evolutionary histories of WFDC8 (short-term balancing) in Europeans and
SPINT4 (incomplete selective sweep) in Africans.. Molecular biology and evolution: 28: 2811-22, 2011
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140. Di Lorito A, Schmitt FC. (Cyto)pathology and sequencing: Next (or last) generation?. Diagnostic cytopathology: , 2011
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141. Lima RT, Seca H, Brás S, Nascimento MS, Vasconcelos MH. Treatment of Akata EBV-positive cells with doxorubicin causes
more EBV reactivation than treatment with etoposide.. Chemotherapy: 57: 195-203, 2011 [10.1159/000323627] [Article]
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142. Moleirinho A, Carneiro J, Matthiesen R, Silva RM, Amorim A, Azevedo L. Gains, losses and changes of function after gene
duplication: study of the metallothionein family.. PloS one: 6: e18487, 2011 [10.1371/journal.pone.0018487] [Article]
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143. Morais P, Mota A, Eloy C, Lopes JM, Torres F, Palmeiro A, Tavares P, Azevedo F. Vascular Ehlers-Danlos syndrome: a case
with fatal outcome.. Dermatology online: 17: 1, 2011 [] [] [IF=2,714]
144. Ferreira M, Evangelista T, Almeida LS, Martins J, Macario MC, Martins E, Moleirinho A, Azevedo L, Vilarinho L, Santorelli
FM. Relative frequency of known causes of multiple mtDNA deletions: two novel POLG mutations.. Neuromuscular
disorders : NMD: 21: 483-8, 2011 [10.1016/j.nmd.2011.03.011] [Article] [IF=2,764]
145. Prazeres H, Couto JP, Rodrigues F, Vinagre J, Torres J, Trovisco V, Martins TC, Sobrinho-Simões M, Soares P. In vitro
transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET protooncogene variants Glu511Lys, Ser649Leu, and Arg886Trp.. Endocrine-related cancer: 18: 401-12, 2011 [10.1530/ERC-100258] [Article] [IF=4,432]
146. Cerqueira L, Fernandes RM, Ferreira RM, Carneiro F, Dinis-Ribeiro M, Figueiredo C, Keevil CW, Azevedo NF, Vieira MJ.
PNA-FISH as a new diagnostic method for the determination of clarithromycin resistance of Helicobacter pylori.. BMC
microbiology: 11: 101, 2011 [10.1186/1471-2180-11-101] [Article] [IF=2,96]
147. Silva Z, Tong Z, Guadalupe Cabral M, Martins C, Castro R, Reis C, Trindade H, Konstantopoulos K, Videira PA. Sialyl
Lewis(x)-dependent binding of human monocyte-derived dendritic cells to selectins.. Biochemical and biophysical
research communications: 409: 459-64, 2011 [10.1016/j.bbrc.2011.05.026] [Article] [IF=2,595]
148. . Melanocytic Tumour in a Black Sheep never exposed to Ultraviolet Radiation.. Journal of comparative pathology: , 2011
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149. Marcos NT, Bennett EP, Gomes J, Magalhaes A, Gomes C, David L, Dar I, Jeanneau C, Defrees S, Krustrup D, Vogel LK, Kure
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150. Musilová E, Fernandes V, Silva NM, Soares P, Alshamali F, Harich N, Cherni L, Gaaied AB, Al-Meeri A, Pereira L, Cerný V.
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mitochondrial DNA HV1 haplogroup.. American journal of physical anthropology: 145: 592-8, 2011 [10.1002/ajpa.21522]
151. Moreira S, Correia M, Soares P, Máximo V. GRIM-19 function in cancer development.. Mitochondrion: 11: 693-9, 2011
[10.1016/j.mito.2011.05.011] [Review] [IF=3,238]
152. Daoud H, Belzil V, Martins S, Sabbagh M, Provencher P, Lacomblez L, Meininger V, Camu W, Dupré N, Dion PA, Rouleau
GA. Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis.. Archives of
neurology: 68: 739-42, 2011 [10.1001/archneurol.2011.111] [Article] [IF=7,108]
153. Simões MJ, Gärtner A, Shirosaki Y, Gil da Costa RM, Cortez PP, Gartnër F, Santos JD, Lopes MA, Geuna S, Varejão AS,
Maurício AC. In vitro and in vivo chitosan membranes testing for peripheral nerve reconstruction.. Acta médica
portuguesa: 24: 43-52, 2011 [] [Article] [IF=0,256]
154. Albuquerque A, Ramalho R, Rios E, Lopes JM, Macedo G. Black esophagus.. Diseases of the esophagus : official journal of
the International Society for Diseases of the Esophagus / I.S.D.E: , 2011 [10.1111/j.1442-2050.2011.01216.x] [Epub ahead
of print] [IF=1,536]
155. Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F, Paredes J. Breast cancer
stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype.. Journal of clinical
pathology: 64: 937-46, 2011 [10.1136/jcp.2011.090456] [Article] [IF=2,475]
156. Rosa C, Araujo R, Rodrigues AG, Pinto-de-Sousa MI, Pina-Vaz C. Detection of Aspergillus species in BACTEC blood cultures..
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157. van Asch B, Silva Santos L, Carneiro J, Pereira F, Amorim A. Identification of mtDNA Lineages of Sus scrofa by Multiplex
Single Base Extension for the Authentication of Processed Food Products.. Journal of agricultural and food chemistry: 59:
6920-6926, 2011 [10.1021/jf201283r] [Article] [IF=2,816]
158. Pértile RA, Moreira S, Costa RM, Correia A, Guardão L, Gartner F, Vilanova M, Gama M. Bacterial Cellulose: Long-Term
Biocompatibility Studies.. Journal of biomaterials science. Polymer edition: , 2011 [10.1163/092050611X581516] [Epub
ahead of print] [IF=1,842]
159. Velho S, Haigis KM. Regulation of homeostasis and oncogenesis in the intestinal epithelium by Ras. Experimental cell
research: 1, 2011 [] [Review] [IF=3,609]
160. Albergaria A, Ricardo S, Milanezi F, Carneiro V, Amendoeira I, Vieira D, Cameselle-Teijeiro J, Schmitt F. Nottingham
Prognostic Index in Triple-Negative Breast Cancer: a reliable prognostic tool?. BMC cancer: 11: 299, 2011 [10.1186/14712407-11-299] [Article] [IF=3,153]
161. Prazeres H, Torres J, Rodrigues F, Couto JP, Vinagre J, Sobrinho-Simões M, Soares P. How to Treat a Signal? Current Basis
for RET-Genotype-Oriented Choice of Kinase Inhibitors for the Treatment of Medullary Thyroid Cancer.. Journal of thyroid
research: 2011: 678357, 2011 [10.4061/2011/678357] [] [IF=0]
92
162. Lopes AM, Arnold-Croop SE, Amorim A, Carrel L. Clustered transcripts that escape X inactivation at mouse XqD..
Mammalian genome : official journal of the International Mammalian Genome Society: 22: 572-82, 2011
[10.1007/s00335-011-9350-6] [Article] [IF=0]
163. Schmitt F, Cochand-Priollet B, Toetsch M, Davidson B, Bondi A, Vielh P. Immunocytochemistry in Europe: results of the
European Federation of Cytology Societies (EFCS) inquiry.. Cytopathology : official journal of the British Society for Clinical
Cytology: 22: 238-42, 2011 [10.1111/j.1365-2303.2011.00885.x] [Article] [IF=1,097]
164. Botelho MC, Machado JC, Brindley PJ, Correia da Costa JM. Targeting molecular signaling pathways of Schistosoma
haemotobium infection in bladder cancer.. Virulence: 2: 267-79, 2011 [] [] [IF=0]
165. Eloy C, Santos J, Soares P, Sobrinho-Simões M. The preeminence of growth pattern and invasiveness and the limited
influence of BRAF and RAS mutations in the occurrence of papillary thyroid carcinoma lymph node metastases.. Virchows
Archiv : an international journal of pathology: 459: 265-76, 2011 [10.1007/s00428-011-1133-7] [Article] [IF=2,336]
166. Gonçalves AP, Videira A, Soares P, Máximo V. Orthovanadate-induced cell death in RET/PTC1-harboring cancer cells
involves the activation of caspases and altered signaling through PI3K/Akt/mTOR.. Life sciences: 89: 371-7, 2011
[10.1016/j.lfs.2011.07.004] [Article] [IF=2,451]
167. Worthley DL, Phillips KD, Wayte N, Schrader KA, Healey S, Kaurah P, Shulkes A, Grimpen F, Clouston A, Moore D, Cullen D,
Ormonde D, Mounkley D, Wen X, Lindor N, Carneiro F, Huntsman DG, Chenevix-Trench G, Suthers GK. Gastric
adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome.. Gut: , 2011
[10.1136/gutjnl-2011-300348] [Epub ahead of print] [IF=10,614]
168. Kijjoa A, Santos S, Dethoup T, Manoch L, Almeida AP, Vasconcelos MH, Silva A, Gales L, Herz W. Sartoryglabrins, analogs of
ardeemins, from Neosartorya glabra.. Natural product communications: 6: 807-12, 2011 [] [Article] [IF=0,894]
169. Reis CA, Campos D, Osório H, Santos LL. Glycopeptide microarray for autoantibody detection in cancer.. Expert review of
proteomics: 8: 435-7, 2011 [10.1586/epr.11.30] [Review] [IF=4,406]
170. Toscanini U, Gusmão L, Berardi G, Gomes V, Amorim A, Salas A, Raimondi E. Male lineages in South American native
groups: evidence of M19 traveling south.. American journal of physical anthropology: 146: 188-96, 2011
[10.1002/ajpa.21562] [Article] [IF=2,693]
171. Sequeiros J, Martins S, Silveira I. Epidemiology and population genetics of degenerative ataxias.. Handbook of clinical
neurology / edited by P.J. Vinken and G.W. Bruyn: 103: 227-51, 2011 [10.1016/B978-0-444-51892-7.00014-0] [] [IF=0]
172. Figueiredo J, Simões-Correia J, Söderberg O, Suriano G, Seruca R. ADP-Ribosylation Factor 6 Mediates E-Cadherin
Recovery by Chemical Chaperones.. PloS one: 6: e23188, 2011 [10.1371/journal.pone.0023188] [Article] [IF=4,411]
173. Goncalves AP, Videira A, Maximo V, Soares P. Synergistic growth inhibition of cancer cells harboring the RET/PTC1
oncogene by staurosporine and rotenone involves enhanced cell death.. Journal of biosciences: 36: 639-48, 2011 []
174. Pinheiro C, Sousa B, Albergaria A, Paredes J, Dufloth R, Vieira D, Schmitt F, Baltazar F. GLUT1 and CAIX expression profiles
in breast cancer correlate with adverse prognostic factors and MCT1 overexpression.. Histology and histopathology: 26:
1279-86, 2011 [] [Article] [IF=2,502]
175. . Identification of new cancer biomarkers based on aberrant mucin glycoforms by in situ Proximity Ligation.. Journal of
cellular and molecular medicine: , 2011 [10.1111/j.1582-4934.2011.01436.x] [Epub ahead of print] [IF=0]
176. Resende C, Thiel A, Machado JC, Ristimäki A. Gastric cancer: basic aspects.. Helicobacter: 16 Suppl 1: 1, 2011
[10.1111/j.1523-5378.2011.00879.x] [Article] [IF=3,109]
177. Albuquerque A, Magro F, Rodrigues S, Lopes J, Lopes S, Dias JM, Carneiro F, Macedo G. Metastatic cutaneous Crohn's
disease of the face: a case report and review of the literature.. European journal of gastroenterology & hepatology: 23:
954-6, 2011 [10.1097/MEG.0b013e328348d706] [Review] [IF=1,598]
178. Borralho PM, Simões AE, Gomes SE, Lima RT, Carvalho T, Ferreira DM, Vasconcelos MH, Castro RE, Rodrigues CM. miR-143
Overexpression Impairs Growth of Human Colon Carcinoma Xenografts in Mice with Induction of Apoptosis and Inhibition
of Proliferation.. PloS one: 6: e23787, 2011 [10.1371/journal.pone.0023787] [Article] [IF=4,411]
179. González CA, Megraud F, Buissoniere A, Lujan Barroso L, Agudo A, Duell EJ, Boutron-Ruault MC, Clavel-Chapelon F, Palli D,
Krogh V, Mattiello A, Tumino R, Sacerdote C, Quirós JR, Sanchez-Cantalejo E, Navarro C, Barricarte A, Dorronsoro M, Khaw
KT, Wareham N, Allen NE, Tsilidis KK, Bas Bueno-de-Mesquita H, Jeurnink SM, Numans ME, Peeters PH, Lagiou P, Valanou
E, Trichopoulou A, Kaaks R, Lukanova-McGregor A, Bergman MM, Boeing H, Manjer J, Lindkvist B, Stenling R, Hallmans G,
Mortensen LM, Overvad K, Olsen A, Tjonneland A, Bakken K, Dumeaux V, Lund E, Jenab M, Romieu I, Michaud D, Mouw T,
Carneiro F, Fenge C, Riboli E. Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric
cancer risk in a prospective study: the Eurgast-EPIC project.. Annals of oncology : official journal of the European Society
for Medical Oncology / ESMO: , 2011 [10.1093/annonc/mdr384] [Epub ahead of print] [IF=0]
180. Costa BM, Viana-Pereira M, Fernandes R, Costa S, Linhares P, Vaz R, Pinheiro C, Lima J, Soares P, Silva A, Pardal F, Amorim
J, Nabiço R, Almeida R, Alegria C, Pires MM, Pinheiro C, Carvalho E, Oliveira P, Lopes JM, Reis RM. Impact of EGFR genetic
variants on glioma risk and patient outcome.. Cancer epidemiology, biomarkers & prevention : a publication of the
American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology: 20: 2610-7,
2011 [10.1158/1055-9965.EPI-11-0340] [Article] [IF=3,919]
181. C Ferreira A, Suriano G, Mendes N, Gomes B, Xiaogang W, Carneiro F, Seruca R, C Machado J. E-cadherin impairment
increases cell survival through Notch-dependent upregulation of Bcl-2. Human molecular genetics: 1, 2011
[10.1093/hmg/ddr469] [] [IF=8,058]
182. Bartosch C, Manuel Lopes J, Oliva E. Endometrial carcinomas: a review emphasizing overlapping and distinctive
morphological and immunohistochemical features.. Advances in anatomic pathology: 18: 415-37, 2011
[10.1097/PAP.0b013e318234ab18] [Review] [IF=3,087]
183. Chajès V, Jenab M, Romieu I, Ferrari P, Dahm CC, Overvad K, Egeberg R, Tjønneland A, Clavel-Chapelon F, Boutron-Ruault
MC, Engel P, Teucher B, Kaaks R, Floegel A, Boeing H, Trichopoulou A, Dilis V, Karapetyan T, Mattiello A, Tumino R, Grioni
S, Palli D, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Lund E, Navarro C, Quirós JR, Sánchez-Cantalejo E, Gurrea AB,
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201.
Dorronsoro M, Regnér S, Sonestedt E, Wirfält E, Khaw KT, Wareham N, Allen NE, Crowe FL, Rinaldi S, Slimani N, Carneiro F,
Riboli E, González CA. Plasma phospholipid fatty acid concentrations and risk of gastric adenocarcinomas in the European
Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).. The American journal of clinical nutrition: 94: 130413, 2011 [10.3945/ajcn.110.005892] [Article] [IF=6,606]
Abreu RMV, Ferreira ICFR, Calhelha RC, Lima RT, Vasconcelos MH, Adega F, Chaves R, Queiroz MJP. Anti-hepatocellular
carcinoma activity using human HepG2 cells and hepatotoxicity of 6-substituted methyl 3-aminothieno[3,2-b]pyridine-2carboxylate derivatives: In vitro evaluation, cell cycle analysis and QSAR studies. European journal of medicinal chemistry:
1, 2011 [10.1016/j.ejmech.2011.09.029] [] [IF=3,193]
Parreira P, Magalhães A, Gonçalves IC, Gomes J, Vidal R, Reis CA, Leckband DE, Martins MC. Effect of surface chemistry on
bacterial adhesion, viability, and morphology.. Journal of biomedical materials research. Part A: 99: 344-353, 2011
[10.1002/jbm.a.33178] [Article] [IF=0]
Fermino ML, Polli CD, Toledo KA, Liu FT, Hsu DK, Roque-Barreira MC, Pereira-da-Silva G, Bernardes ES, HalbwachsMecarelli L. LPS-induced galectin-3 oligomerization results in enhancement of neutrophil activation.. PloS one: 6: e26004,
2011 [10.1371/journal.pone.0026004] [Article] [IF=4,411]
Schmitt F, Barroca H. Role of ancillary studies in fine-needle aspiration from selected tumors.. Cancer cytopathology: ,
2011 [10.1002/cncy.20197] [Epub ahead of print] [IF=0]
Diagnostic challenges of Marfan syndrome in an XYY young man.. Cardiology in the young: 40969, 2011
[10.1017/S1047951111001776] [Epub ahead of print] [IF=0,858]
Lopes-Marques M, Pereira-Castro I, Amorim A, Azevedo L. Characterization of the Human Ornithine Transcarbamylase 3'
Untranslated Regulatory Region.. DNA and cell biology: , 2011 [10.1089/dna.2011.1391] [Epub ahead of print] [IF=2,159]
Serafini M, Jakszyn P, Luján-Barroso L, Agudo A, Bueno-de-Mesquita HB, van Duijnhoven FJ, Jenab M, Navarro C, Palli D,
Boeing H, Wallström P, Regnér S, Numans ME, Carneiro F, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Grioni S,
Panico S, Tumino R, Sacerdote C, Quirós JR, Molina-Montes E, Huerta Castaño JM, Barricarte A, Amiano P, Khaw KT,
Wareham N, Allen NE, Key TJ, Jeurnink SM, Peeters PH, Bamia C, Valanou E, Trichopoulou A, Kaaks R, Lukanova A,
Bergmann MM, Lindkvist B, Stenling R, Johansson I, Dahm CC, Overvad K, Jensen M, Olsen A, Tjonneland A, Lund E, Rinaldi
S, Michaud D, Mouw T, Riboli E, González CA. Dietary total antioxidant capacity and gastric cancer risk in the european
prospective investigation into cancer and nutrition study.. International journal of cancer. Journal international du cancer:
, 2011 [10.1002/ijc.27347] [Epub ahead of print] [IF=4,926]
Eloy C, Santos J, Soares P, Sobrinho-Simões M. Intratumoural lymph vessel density is related to presence of lymph node
metastases and separates encapsulated from infiltrative papillary thyroid carcinoma.. Virchows Archiv : an international
journal of pathology: 459: 595-605, 2011 [10.1007/s00428-011-1161-3] [Article] [IF=2,336]
Schmitt FC. Molecular cytopathology and flow cytometry: pre-analytical procedures matter.. Cytopathology : official
journal of the British Society for Clinical Cytology: 22: 1, 2011 [10.1111/j.1365-2303.2011.00941.x] [Editorial Material]
[IF=1,097]
Beites T, Pires SD, Santos CL, Osório H, Moradas-Ferreira P, Mendes MV. Crosstalk between ROS Homeostasis and
Secondary Metabolism in S. natalensis ATCC 27448: Modulation of Pimaricin Production by Intracellular ROS.. PloS one: 6:
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Romanini C, Catelli ML, Borosky A, Pereira R, Romero M, Salado Puerto M, Phillips C, Fondevila M, Freire A, Santos C,
Carracedo A, Lareu MV, Gusmao L, Vullo CM. Typing short amplicon binary polymorphisms: Supplementary SNP and Indel
genetic information in the analysis of highly degraded skeletal remains.. Forensic science international. Genetics: , 2011
[10.1016/j.fsigen.2011.10.006] [Epub ahead of print] [IF=2,877]
Dina R, Gudi M, Kocjan G, Schmitt F, Vielh P. The danger to cytopathology of over-specialization and its relevance for
histopathology.. Cytopathology : official journal of the British Society for Clinical Cytology: 22: 139-40, 2011
[10.1111/j.1365-2303.2011.00865.x] [Letter] [IF=1,097]
Gomes J, Magalhães A, Valérie M, Amado I, Aranha P, Ovesen RG, Hansen HCB, Gartner F, Reis C A, Touati E. Pteridium
aquillinum and its ptaquiloside toxin induce DNA damage response in gastric epithelial cells, a link with gastric
carcinogenesis.. Toxicological Sciences: 1, 2011 [10.1093/toxsci/kfr329] [] [IF=5,093]
Pareja F, Ferraro DA, Rubin C, Cohen-Dvashi H, Zhang F, Aulmann S, Ben-Chetrit N, Pines G, Navon R, Crosetto N, Köstler
W, Carvalho S, Lavi S, Schmitt F, Dikic I, Yakhini Z, Sinn P, Mills GB, Yarden Y. Deubiquitination of EGFR by Cezanne-1
contributes to cancer progression.. Oncogene: 1, 2011 [10.1038/onc.2011.587] [] [IF=7,414]
Lopes N, Carvalho J, Durães C, Sousa B, Gomes M, Costa JL, Oliveira C, Paredes J, Schmitt F. 1alpha,25-dihydroxyvitamin
D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1 promoter demethylation.
Anticancer research: 1, 2011 [] [] [IF=1,656]
Ferreira RM, Figueiredo C, Bonet C, Pardo ML, Ruiz Liso JM, Alonso P, Sala N, Capella G, Sanz-Anquela JM, Gonzalez CA.
Helicobacter pylori vacA intermediate region genotyping and progression of gastric preneoplastic lesions. The American
journal of gastroenterology: 1, 2011 [] [] [IF=6,882]
Caplin M, Lopes JM, Sundin A, Nillson O, Baum RP, Klose KJ, Kelestimur F, Plöckinger U, Papotti M, Salazar R, Pascher A.
ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms: Colorectal
Neuroendocrine Neoplasms.. Neuroendocrinology: , 2011 [10.1159/000335594] [Epub ahead of print] [IF=3,272]
Fernandes V, Alshamali F, Alves M, Costa MD, Pereira JB, Silva NM, Cherni L, Harich N, Cerny V, Soares P, Richards MB,
Pereira L. The Arabian Cradle: Mitochondrial Relicts of the First Steps along the Southern Route out of Africa.. American
journal of human genetics: 90: 347-55, 2011 [10.1016/j.ajhg.2011.12.010] [] [IF=11,68]
94
MEMBERS OF IPATIMUP AT EDITORIAL BOARDS

Research in Cancer and Tumor

World Journal of Clinical Infectious Diseases

The Scientific World Journal
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Frontiers in Genomic Assay Technology

World Journal of Gastroenterology

Journal of Integrated OMICS

World Journal of Biological Chemistry

Ultrastructural Pathology

Seminars in Diagnostic Pathology

Patologia
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Pathology, Research and Practice
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Open Pathology Journal
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Journal of Pathology
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Histopathology
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European Journal of Cancer Prevention
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Current Diagnostic Pathology
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The Open Forensic Science Jounal
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